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9.1A: Signaling Molecules and Cellular Receptors - Biology

9.1A: Signaling Molecules and Cellular Receptors - Biology


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Cellular communication ensures regulation of biological processes within various environments from single-celled to multicellular organisms.

Learning Objectives

  • Explain the importance of cell communication

Key Points

  • The ability of cells to communicate through chemical signals originated in single cells and was essential for the evolution of multicellular organisms.
  • In multicellular organisms, cells send and receive chemical messages constantly to coordinate the actions of distant organs, tissues, and cells.
  • Cells can receive a message, transfer the information across the plasma membrane, and then produce changes within the cell in response to the message.
  • Single-celled organisms, like yeast and bacteria, communicate with each other to aid in mating and coordination.
  • Cellular communication has developed as a means to communicate with the environment, produce biological changes, and, if necessary, ensure survival.

Key Terms

  • biofilm: a thin film of mucus created by and containing a colony of bacteria and other microorganisms

Introduction: Signaling Molecules and Cellular Receptors

Imagine what life would be like if you and the people around you could not communicate. You would not be able to express your wishes to others, nor could you ask questions to find out more about your environment. Social organization is dependent on communication between the individuals that comprise that society; without communication, society would fall apart.

As with people, it is vital for individual cells to be able to interact with their environment. This is true whether a cell is growing by itself in a pond or is one of many cells that form a larger organism. In order to properly respond to external stimuli, cells have developed complex mechanisms of communication that can receive a message, transfer the information across the plasma membrane, and then produce changes within the cell in response to the message.

In multicellular organisms, cells send and receive chemical messages constantly to coordinate the actions of distant organs, tissues, and cells. The ability to send messages quickly and efficiently enables cells to coordinate and fine-tune their functions.

While the necessity for cellular communication in larger organisms seems obvious, even single-celled organisms communicate with each other. Yeast cells signal each other to aid mating. Some forms of bacteria coordinate their actions in order to form large complexes called biofilms or to organize the production of toxins to remove competing organisms. The ability of cells to communicate through chemical signals originated in single cells and was essential for the evolution of multicellular organisms. The efficient and error-free function of communication systems is vital for all forms of life.


Figure 1. Hydrophobic signaling molecules typically diffuse across the plasma membrane and interact with intracellular receptors in the cytoplasm. Many intracellular receptors are transcription factors that interact with DNA in the nucleus and regulate gene expression.

Internal receptors, also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane. Once inside the cell, many of these molecules bind to proteins that act as regulators of mRNA synthesis (transcription) to mediate gene expression. Gene expression is the cellular process of transforming the information in a cell’s DNA into a sequence of amino acids, which ultimately forms a protein. When the ligand binds to the internal receptor, a conformational change is triggered that exposes a DNA-binding site on the protein. The ligand-receptor complex moves into the nucleus, then binds to specific regulatory regions of the chromosomal DNA and promotes the initiation of transcription (Figure 1). Transcription is the process of copying the information in a cell’s DNA into a special form of RNA called messenger RNA (mRNA) the cell uses information in the mRNA (which moves out into the cytoplasm and associates with ribosomes) to link specific amino acids in the correct order, producing a protein. Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or messengers.


Forms of Signaling

There are four categories of chemical signaling found in multicellular organisms: paracrine signaling, endocrine signaling, autocrine signaling, and direct signaling across gap junctions (Figure). The main difference between the different categories of signaling is the distance that the signal travels through the organism to reach the target cell. Not all cells are affected by the same signals.

In chemical signaling, a cell may target itself (autocrine signaling), a cell connected by gap junctions, a nearby cell (paracrine signaling), or a distant cell (endocrine signaling). Paracrine signaling acts on nearby cells, endocrine signaling uses the circulatory system to transport ligands, and autocrine signaling acts on the signaling cell. Signaling via gap junctions involves signaling molecules moving directly between adjacent cells.


Biology 171


Imagine what life would be like if you and the people around you could not communicate. You would not be able to express your wishes to others, nor could you ask questions about your location. Social organization is dependent on communication between the individuals that comprise that society without communication, society would fall apart.

As with people, it is vital for individual cells to be able to interact with their environment. This is true for both a one-celled organism growing in a puddle and a large animal living on a savanna. In order to properly respond to external stimuli, cells have developed complex mechanisms of communication that can receive a message, transfer the information across the plasma membrane, and then produce changes within the cell in response to the message.

In multicellular organisms, cells send and receive chemical messages constantly to coordinate the actions of distant organs, tissues, and cells. The ability to send messages quickly and efficiently enables cells to coordinate and fine-tune their functions.

While the necessity for cellular communication in larger organisms seems obvious, even single-celled organisms communicate with each other. Yeast cells signal each other to aid in finding other yeast cells for reproduction. Some forms of bacteria coordinate their actions in order to form large complexes called biofilms or to organize the production of toxins to remove competing organisms. The ability of cells to communicate through chemical signals originated in single cells and was essential for the evolution of multicellular organisms. The efficient and relatively error-free function of communication systems is vital for all life as we know it.

Learning Objectives

By the end of this section, you will be able to do the following:

  • Describe four types of signaling mechanisms found in multicellular organisms
  • Compare internal receptors with cell-surface receptors
  • Recognize the relationship between a ligand’s structure and its mechanism of action

There are two kinds of communication in the world of living cells. Communication between cells is called intercellular signaling , and communication within a cell is called intracellular signaling . An easy way to remember the distinction is by understanding the Latin origin of the prefixes: inter- means “between” (for example, intersecting lines are those that cross each other) and intra- means “inside” (as in intravenous).

Chemical signals are released by signaling cells in the form of small, usually volatile or soluble molecules called ligands. A ligand is a molecule that binds another specific molecule, in some cases, delivering a signal in the process. Ligands can thus be thought of as signaling molecules. Ligands interact with proteins in target cells , which are cells that are affected by chemical signals these proteins are also called receptors . Ligands and receptors exist in several varieties however, a specific ligand will have a specific receptor that typically binds only that ligand.

Forms of Signaling

There are four categories of chemical signaling found in multicellular organisms: paracrine signaling, endocrine signaling, autocrine signaling, and direct signaling across gap junctions ((Figure)). The main difference between the different categories of signaling is the distance that the signal travels through the organism to reach the target cell. We should note here that not all cells are affected by the same signals.


Paracrine Signaling

Signals that act locally between cells that are close together are called paracrine signals . Paracrine signals move by diffusion through the extracellular matrix. These types of signals usually elicit quick responses that last only a short period of time. In order to keep the response localized, paracrine ligand molecules are normally quickly degraded by enzymes or removed by neighboring cells. Removing the signals will reestablish the concentration gradient for the signal, allowing them to quickly diffuse through the intracellular space if released again.

One example of paracrine signaling is the transfer of signals across synapses between nerve cells. A nerve cell consists of a cell body, several short, branched extensions called dendrites that receive stimuli, and a long extension called an axon, which transmits signals to other nerve cells or muscle cells. The junction between nerve cells where signal transmission occurs is called a synapse. A synaptic signal is a chemical signal that travels between nerve cells. Signals within the nerve cells are propagated by fast-moving electrical impulses. When these impulses reach the end of the axon, the signal continues on to a dendrite of the next cell by the release of chemical ligands called neurotransmitters from the presynaptic cell (the cell emitting the signal). The neurotransmitters are transported across the very small distances (20–40 nanometers) between nerve cells, which are called chemical synapses ((Figure)). The small distance between nerve cells allows the signal to travel quickly this enables an immediate response, such as, “Take your hand off the stove!”

When the neurotransmitter binds the receptor on the surface of the postsynaptic cell, the electrochemical potential of the target cell changes, and the next electrical impulse is launched. The neurotransmitters that are released into the chemical synapse are degraded quickly or get reabsorbed by the presynaptic cell so that the recipient nerve cell can recover quickly and be prepared to respond rapidly to the next synaptic signal.


Endocrine Signaling

Signals from distant cells are called endocrine signals , and they originate from endocrine cells . (In the body, many endocrine cells are located in endocrine glands, such as the thyroid gland, the hypothalamus, and the pituitary gland.) These types of signals usually produce a slower response but have a longer-lasting effect. The ligands released in endocrine signaling are called hormones, signaling molecules that are produced in one part of the body but affect other body regions some distance away.

Hormones travel the large distances between endocrine cells and their target cells via the bloodstream, which is a relatively slow way to move throughout the body. Because of their form of transport, hormones become diluted and are present in low concentrations when they act on their target cells. This is different from paracrine signaling, in which local concentrations of ligands can be very high.

Autocrine Signaling

Autocrine signals are produced by signaling cells that can also bind to the ligand that is released. This means the signaling cell and the target cell can be the same or a similar cell (the prefix auto- means self, a reminder that the signaling cell sends a signal to itself). This type of signaling often occurs during the early development of an organism to ensure that cells develop into the correct tissues and take on the proper function. Autocrine signaling also regulates pain sensation and inflammatory responses. Further, if a cell is infected with a virus, the cell can signal itself to undergo programmed cell death, killing the virus in the process. In some cases, neighboring cells of the same type are also influenced by the released ligand. In embryological development, this process of stimulating a group of neighboring cells may help to direct the differentiation of identical cells into the same cell type, thus ensuring the proper developmental outcome.

Direct Signaling Across Gap Junctions

Gap junctions in animals and plasmodesmata in plants are connections between the plasma membranes of neighboring cells. These fluid-filled channels allow small signaling molecules, called intracellular mediators , to diffuse between the two cells. Small molecules, such as calcium ions (Ca 2+ ), are able to move between cells, but large molecules like proteins and DNA cannot fit through the channels. The specificity of the channels ensures that the cells remain independent but can quickly and easily transmit signals. The transfer of signaling molecules communicates the current state of the cell that is directly next to the target cell this allows a group of cells to coordinate their response to a signal that only one of them may have received. In plants, plasmodesmata are ubiquitous, making the entire plant into a giant communication network.

Types of Receptors

Receptors are protein molecules in the target cell or on its surface that bind ligand. There are two types of receptors, internal receptors and cell-surface receptors.

Internal receptors

Internal receptors , also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane. Once inside the cell, many of these molecules bind to proteins that act as regulators of mRNA synthesis (transcription) to mediate gene expression. Gene expression is the cellular process of transforming the information in a cell’s DNA into a sequence of amino acids, which ultimately forms a protein. When the ligand binds to the internal receptor, a conformational change is triggered that exposes a DNA-binding site on the protein. The ligand-receptor complex moves into the nucleus, then binds to specific regulatory regions of the chromosomal DNA and promotes the initiation of transcription ((Figure)). Transcription is the process of copying the information in a cell’s DNA into a special form of RNA called messenger RNA (mRNA) the cell uses information in the mRNA (which moves out into the cytoplasm and associates with ribosomes) to link specific amino acids in the correct order, producing a protein. Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or messengers.


Cell-Surface Receptors

Cell-surface receptors , also known as transmembrane receptors, are cell surface, membrane-anchored (integral) proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, through which an extracellular signal is converted into an intracellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.

Because cell-surface receptor proteins are fundamental to normal cell functioning, it should come as no surprise that a malfunction in any one of these proteins could have severe consequences. Errors in the protein structures of certain receptor molecules have been shown to play a role in hypertension (high blood pressure), asthma, heart disease, and cancer.

Each cell-surface receptor has three main components: an external ligand-binding domain, a hydrophobic membrane-spanning region called a transmembrane domain, and an intracellular domain inside the cell. The ligand-binding domain is also called the extracellular domain . The size and extent of each of these domains vary widely, depending on the type of receptor.

How Viruses Recognize a Host Unlike living cells, many viruses do not have a plasma membrane or any of the structures necessary to sustain metabolic life. Some viruses are simply composed of an inert protein shell enclosing DNA or RNA. To reproduce, viruses must invade a living cell, which serves as a host, and then take over the hosts cellular apparatus. But how does a virus recognize its host?

Viruses often bind to cell-surface receptors on the host cell. For example, the virus that causes human influenza (flu) binds specifically to receptors on membranes of cells of the respiratory system. Chemical differences in the cell-surface receptors among hosts mean that a virus that infects a specific species (for example, humans) often cannot infect another species (for example, chickens).

However, viruses have very small amounts of DNA or RNA compared to humans, and, as a result, viral reproduction can occur rapidly. Viral reproduction invariably produces errors that can lead to changes in newly produced viruses these changes mean that the viral proteins that interact with cell-surface receptors may evolve in such a way that they can bind to receptors in a new host. Such changes happen randomly and quite often in the reproductive cycle of a virus, but the changes only matter if a virus with new binding properties comes into contact with a suitable host. In the case of influenza, this situation can occur in settings where animals and people are in close contact, such as poultry and swine farms. 1 Once a virus jumps the former “species barrier” to a new host, it can spread quickly. Scientists watch newly appearing viruses (called emerging viruses) closely in the hope that such monitoring can reduce the likelihood of global viral epidemics.

Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors, and enzyme-linked receptors.

Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through. To form a channel, this type of cell-surface receptor has an extensive membrane-spanning region. In order to interact with the double layer of phospholipid fatty acid tails that form the center of the plasma membrane, many of the amino acids in the membrane-spanning region are hydrophobic in nature. Conversely, the amino acids that line the inside of the channel are hydrophilic to allow for the passage of water or ions. When a ligand binds to the extracellular region of the channel, there is a conformational change in the protein’s structure that allows ions such as sodium, calcium, magnesium, and hydrogen to pass through ((Figure)).


G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane ((Figure)). All G-protein-linked receptors have seven transmembrane domains, but each receptor has its own specific extracellular domain and G-protein-binding site.

Cell signaling using G-protein-linked receptors occurs as a cyclic series of events. Before the ligand binds, the inactive G-protein can bind to a newly revealed site on the receptor specific for its binding. Once the G-protein binds to the receptor, the resulting change in shape activates the G-protein, which releases guanosine diposphate (GDP) and picks up guanosine 3-phosphate (GTP). The subunits of the G-protein then split into the α subunit and the βγ subunit. One or both of these G-protein fragments may be able to activate other proteins as a result. After awhile, the GTP on the active α subunit of the G-protein is hydrolyzed to GDP and the βγ subunit is deactivated. The subunits reassociate to form the inactive G-protein and the cycle begins anew.


G-protein-linked receptors have been extensively studied and much has been learned about their roles in maintaining health. Bacteria that are pathogenic to humans can release poisons that interrupt specific G-protein-linked receptor function, leading to illnesses such as pertussis, botulism, and cholera. In cholera ((Figure)), for example, the water-borne bacterium Vibrio cholerae produces a toxin, choleragen, that binds to cells lining the small intestine. The toxin then enters these intestinal cells, where it modifies a G-protein that controls the opening of a chloride channel and causes it to remain continuously active, resulting in large losses of fluids from the body and potentially fatal dehydration as a result.


Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme. In some cases, the intracellular domain of the receptor itself is an enzyme. Other enzyme-linked receptors have a small intracellular domain that interacts directly with an enzyme. The enzyme-linked receptors normally have large extracellular and intracellular domains, but the membrane-spanning region consists of a single alpha-helical region of the peptide strand. When a ligand binds to the extracellular domain, a signal is transferred through the membrane, activating the enzyme. Activation of the enzyme sets off a chain of events within the cell that eventually leads to a response. One example of this type of enzyme-linked receptor is the tyrosine kinase receptor ((Figure)). A kinase is an enzyme that transfers phosphate groups from ATP to another protein. The tyrosine kinase receptor transfers phosphate groups to tyrosine molecules (tyrosine residues). First, signaling molecules bind to the extracellular domain of two nearby tyrosine kinase receptors. The two neighboring receptors then bond together, or dimerize. Phosphates are then added to tyrosine residues on the intracellular domain of the receptors (phosphorylation). The phosphorylated residues can then transmit the signal to the next messenger within the cytoplasm.


HER2 is a receptor tyrosine kinase. In 30 percent of human breast cancers, HER2 is permanently activated, resulting in unregulated cell division. Lapatinib, a drug used to treat breast cancer, inhibits HER2 receptor tyrosine kinase autophosphorylation (the process by which the receptor adds phosphates onto itself), thus reducing tumor growth by 50 percent. Besides autophosphorylation, which of the following steps would be inhibited by Lapatinib?

  1. Signaling molecule binding, dimerization, and the downstream cellular response
  2. Dimerization, and the downstream cellular response
  3. The downstream cellular response
  4. Phosphatase activity, dimerization, and the downsteam cellular response

Signaling Molecules

Produced by signaling cells and the subsequent binding to receptors in target cells, ligands act as chemical signals that travel to the target cells to coordinate responses. The types of molecules that serve as ligands are incredibly varied and range from small proteins to small ions like calcium (Ca 2+ ).

Small Hydrophobic Ligands

Small hydrophobic ligands can directly diffuse through the plasma membrane and interact with internal receptors. Important members of this class of ligands are the steroid hormones. Steroids are lipids that have a hydrocarbon skeleton with four fused rings different steroids have different functional groups attached to the carbon skeleton. Steroid hormones include the female sex hormone, estradiol, which is a type of estrogen the male sex hormone, testosterone and cholesterol, which is an important structural component of biological membranes and a precursor of steriod hormones ((Figure)). Other hydrophobic hormones include thyroid hormones and vitamin D. In order to be soluble in blood, hydrophobic ligands must bind to carrier proteins while they are being transported through the bloodstream.


Water-Soluble Ligands

Water-soluble ligands are polar and, therefore, cannot pass through the plasma membrane unaided sometimes, they are too large to pass through the membrane at all. Instead, most water-soluble ligands bind to the extracellular domain of cell-surface receptors. This group of ligands is quite diverse and includes small molecules, peptides, and proteins.

Other Ligands

Nitric oxide (NO) is a gas that also acts as a ligand. It is able to diffuse directly across the plasma membrane, and one of its roles is to interact with receptors in smooth muscle and induce relaxation of the tissue. NO has a very short half-life and, therefore, only functions over short distances. Nitroglycerin, a treatment for heart disease, acts by triggering the release of NO, which causes blood vessels to dilate (expand), thus restoring blood flow to the heart. NO has become better known recently because the pathway that it affects is targeted by prescription medications for erectile dysfunction, such as Viagra (erection involves dilated blood vessels).

Section Summary

Cells communicate by both inter- and intracellular signaling. Signaling cells secrete ligands that bind to target cells and initiate a chain of events within the target cell. The four categories of signaling in multicellular organisms are paracrine signaling, endocrine signaling, autocrine signaling, and direct signaling across gap junctions. Paracrine signaling takes place over short distances. Endocrine signals are carried long distances through the bloodstream by hormones, and autocrine signals are received by the same cell that sent the signal or other nearby cells of the same kind. Gap junctions allow small molecules, including signaling molecules, to flow between neighboring cells.

Internal receptors are found in the cell cytoplasm. Here, they bind ligand molecules that cross the plasma membrane these receptor-ligand complexes move to the nucleus and interact directly with cellular DNA. Cell-surface receptors transmit a signal from outside the cell to the cytoplasm. Ion channel-linked receptors, when bound to their ligands, form a pore through the plasma membrane through which certain ions can pass. G-protein-linked receptors interact with a G-protein on the cytoplasmic side of the plasma membrane, promoting the exchange of bound GDP for GTP and interacting with other enzymes or ion channels to transmit a signal. Enzyme-linked receptors transmit a signal from outside the cell to an intracellular domain of a membrane-bound enzyme. Ligand binding causes activation of the enzyme. Small hydrophobic ligands (like steroids) are able to penetrate the plasma membrane and bind to internal receptors. Water-soluble hydrophilic ligands are unable to pass through the membrane instead, they bind to cell-surface receptors, which transmit the signal to the inside of the cell.

Art Connections

(Figure) HER2 is a receptor tyrosine kinase. In 30 percent of human breast cancers, HER2 is permanently activated, resulting in unregulated cell division. Lapatinib, a drug used to treat breast cancer, inhibits HER2 receptor tyrosine kinase autophosphorylation (the process by which the receptor adds phosphates onto itself), thus reducing tumor growth by 50 percent. Besides autophosphorylation, which of the following steps would be inhibited by Lapatinib?

  1. Signaling molecule binding, dimerization, and the downstream cellular response.
  2. Dimerization, and the downstream cellular response.
  3. The downstream cellular response.
  4. Phosphatase activity, dimerization, and the downsteam cellular response.

(Figure) C. The downstream cellular response would be inhibited.

Free Response

What is the difference between intracellular signaling and intercellular signaling?

Intracellular signaling occurs within a cell, and intercellular signaling occurs between cells.

How are the effects of paracrine signaling limited to an area near the signaling cells?

The secreted ligands are quickly removed by degradation or reabsorption into the cell so that they cannot travel far.

What are the differences between internal receptors and cell-surface receptors?

Internal receptors are located inside the cell, and their ligands enter the cell to bind the receptor. The complex formed by the internal receptor and the ligand then enters the nucleus and directly affects protein production by binding to the chromosomal DNA and initiating the making of mRNA that codes for proteins. Cell-surface receptors, however, are embedded in the plasma membrane, and their ligands do not enter the cell. Binding of the ligand to the cell-surface receptor initiates a cell signaling cascade and does not directly influence the making of proteins however, it may involve the activation of intracellular proteins.

Cells grown in the laboratory are mixed with a dye molecule that is unable to pass through the plasma membrane. If a ligand is added to the cells, observations show that the dye enters the cells. What type of receptor did the ligand bind to on the cell surface?

An ion channel receptor opened up a pore in the membrane, which allowed the ionic dye to move into the cell.

Insulin is a hormone that regulates blood sugar by binding to its receptor, insulin receptor tyrosine kinase. How does insulin’s behavior differ from steroid hormone signaling, and what can you infer about its structure?

Insulin’s receptor is an enzyme-linked transmembrane receptor, as can be determined from the “tyrosine kinase” in its name. This receptor is embedded in the plasma membrane, and insulin binds to its extracellular (outer) surface to initiate intracellular signaling cascades.

Normally, steroid hormones cross the plasma membrane to bind with intracellular receptors. These intracellular hormone-receptor complexes then interact directly with DNA to regulate transcription. This limits steroid hormones to be small, non-polar molecules so they can cross the plasma membrane. However, since insulin does not have to cross into the cell it could be large or polar (it is a small, polar molecule).

Footnotes

    A. B. Sigalov, The School of Nature. IV. Learning from Viruses, Self/Nonself 1, no. 4 (2010): 282-298. Y. Cao, X. Koh, L. Dong, X. Du, A. Wu, X. Ding, H. Deng, Y. Shu, J. Chen, T. Jiang, Rapid Estimation of Binding Activity of Influenza Virus Hemagglutinin to Human and Avian Receptors, PLoS One 6, no. 4 (2011): e18664.

Glossary


9.1 Signalling Molecules and Cellular Receptors

In this section, you will explore the following questions:

  • What are the four types of signaling that are found in multicellular organisms?
  • What are the differences between internal receptors and cell-surface receptors?
  • What is the relationship between a ligand’s structure and its mechanism of action?

Connection for AP ® Courses

Just like you communicate with your classmates face-to-face, using your phone, or via e-mail, cells communicate with each other by both inter’and intracellular signaling. Cells detect and respond to changes in the environment using signaling pathways. Signaling pathways enable organisms to coordinate cellular activities and metabolic processes. Errors in these pathways can cause disease. Signaling cells secrete molecules called ligands that bind to target cells and initiate a chain of events within the target cell. For example, when epinephrine is released, binding to target cells, those cells respond by converting glycogen to glucose. Cell communication can happen over short distances. For example, neurotransmitters are released across a synapse to transfer messages between neurons (Figure 26.15). Gap junctions and plasmodesmata allow small molecules, including signaling molecules, to flow between neighboring cells. Cell communication can also happen over long distances using. For example, hormones released from endocrine cells travel to target cells in multiple body systems. How does a ligand such as a hormone traveling through the bloodstream “know” when it has reached its target organ to initiate a cellular response? Nearly all cell signaling pathways involve three stages: reception, signal transduction, and cellular response.

Cell signaling pathways begin when the ligand binds to a receptor, a protein that is embedded in the plasma membrane of the target cell or found in the cell cytoplasm. The receptors are very specific, and each ligand is recognized by a different one. This stage of the pathway is called reception. Molecules that are nonpolar, such as steroids, diffuse across the cell membrane and bind to internal receptors. In turn, the receptor-ligand complex moves to the nucleus and interacts with cellular DNA. This changes how a gene is expressed. Polar ligands, on the other hand, interact with membrane receptor protein. Some membrane receptors work by changing conformation so that certain ions, such as Na + and K + , can pass through the plasma membrane. Other membrane receptors interact with a G-protein on the cytoplasmic side of the plasma membrane, which causes a series of reactions inside the cell. Disruptions to this process are linked to several diseases, including cholera.

It is important to keep in mind that each cell has a variety of receptors, allowing it to respond to a variety of stimuli. Some receptors can bind several different ligands for example, odorant molecules/receptors associated with the sense of smell in animals. Once the signaling molecule and receptor interact, a cascade of events called signal transduction usually amplifies the signal inside the cell.

The content presented in this section supports the Learning Objectives outlined in Big Idea 3 of the AP ® Biology Curriculum Framework listed. The AP ® Learning Objectives merge Essential knowledge content with one or more of the seven Science Practices. These objectives provide a transparent foundation for the AP ® Biology course, along with inquiry-based laboratory experiences, instructional activities, and AP ® Exam questions.

Big Idea 3 Living systems store, retrieve, transmit and respond to information essential to life processes.
Enduring Understanding 3.D Cells communicate by generating, transmitting and receiving chemical signals.
Essential Knowledge 3.D.3 Signal transduction pathways link signal reception with cellular response.
Science Practice 6.2 The student can construct explanations of phenomena based on evidence produced through scientific practices.
Learning Objective 3.34 The student is able to construct explanations of cell communication through cell-to-cell direct contact or through chemical signaling.
Essential Knowledge 3.D.3 Signal transduction pathways link signal reception with cellular response.
Science Practice 1.1 The student can create representations and models of natural or man-made phenomena and systems in the domain.
Learning Objective 3.35 The student is able to create representations that depict how cell-to-cell communication occurs by direct contact or from a distance through chemical signaling.

The Science Practice Challenge Questions contain contains additional test questions for this section that will help you prepare for the AP exam. These questions address the following standards:
[APLO 3.33][APLO 3.36]

There are two kinds of communication in the world of living cells. Communication between cells is called intercellular signaling , and communication within a cell is called intracellular signaling . An easy way to remember the distinction is by understanding the Latin origin of the prefixes: inter- means "between" (for example, intersecting lines are those that cross each other) and intra- means "inside" (like intravenous).

Chemical signals are released by signaling cells in the form of small, usually volatile or soluble molecules called ligands. A ligand is a molecule that binds another specific molecule, in some cases, delivering a signal in the process. Ligands can thus be thought of as signaling molecules. Ligands interact with proteins in target cells , which are cells that are affected by chemical signals these proteins are also called receptors . Ligands and receptors exist in several varieties however, a specific ligand will have a specific receptor that typically binds only that ligand.

Forms of Signaling

There are four categories of chemical signaling found in multicellular organisms: paracrine signaling, endocrine signaling, autocrine signaling, and direct signaling across gap junctions (Figure 9.2). The main difference between the different categories of signaling is the distance that the signal travels through the organism to reach the target cell. Not all cells are affected by the same signals.

Paracrine Signaling

Signals that act locally between cells that are close together are called paracrine signals . Paracrine signals move by diffusion through the extracellular matrix. These types of signals usually elicit quick responses that last only a short amount of time. In order to keep the response localized, paracrine ligand molecules are normally quickly degraded by enzymes or removed by neighboring cells. Removing the signals will reestablish the concentration gradient for the signal, allowing them to quickly diffuse through the intracellular space if released again.

One example of paracrine signaling is the transfer of signals across synapses between nerve cells. A nerve cell consists of a cell body, several short, branched extensions called dendrites that receive stimuli, and a long extension called an axon, which transmits signals to other nerve cells or muscle cells. The junction between nerve cells where signal transmission occurs is called a synapse. A synaptic signal is a chemical signal that travels between nerve cells. Signals within the nerve cells are propagated by fast-moving electrical impulses. When these impulses reach the end of the axon, the signal continues on to a dendrite of the next cell by the release of chemical ligands called neurotransmitters by the presynaptic cell (the cell emitting the signal). The neurotransmitters are transported across the very small distances between nerve cells, which are called chemical synapses (Figure 9.3). The small distance between nerve cells allows the signal to travel quickly this enables an immediate response, such as, Take your hand off the stove!

When the neurotransmitter binds the receptor on the surface of the postsynaptic cell, the electrochemical potential of the target cell changes, and the next electrical impulse is launched. The neurotransmitters that are released into the chemical synapse are degraded quickly or get reabsorbed by the presynaptic cell so that the recipient nerve cell can recover quickly and be prepared to respond rapidly to the next synaptic signal.

Endocrine Signaling

Signals from distant cells are called endocrine signals , and they originate from endocrine cells . (In the body, many endocrine cells are located in endocrine glands, such as the thyroid gland, the hypothalamus, and the pituitary gland.) These types of signals usually produce a slower response but have a longer-lasting effect. The ligands released in endocrine signaling are called hormones, signaling molecules that are produced in one part of the body but affect other body regions some distance away.

Hormones travel the large distances between endocrine cells and their target cells via the bloodstream, which is a relatively slow way to move throughout the body. Because of their form of transport, hormones get diluted and are present in low concentrations when they act on their target cells. This is different from paracrine signaling, in which local concentrations of ligands can be very high.

Autocrine Signaling

Autocrine signals are produced by signaling cells that can also bind to the ligand that is released. This means the signaling cell and the target cell can be the same or a similar cell (the prefix auto- means self, a reminder that the signaling cell sends a signal to itself). This type of signaling often occurs during the early development of an organism to ensure that cells develop into the correct tissues and take on the proper function. Autocrine signaling also regulates pain sensation and inflammatory responses. Further, if a cell is infected with a virus, the cell can signal itself to undergo programmed cell death, killing the virus in the process. In some cases, neighboring cells of the same type are also influenced by the released ligand. In embryological development, this process of stimulating a group of neighboring cells may help to direct the differentiation of identical cells into the same cell type, thus ensuring the proper developmental outcome.

Direct Signaling Across Gap Junctions

Gap junctions in animals and plasmodesmata in plants are connections between the plasma membranes of neighboring cells. These fluid-filled channels allow small signaling molecules, called intracellular mediators , to diffuse between the two cells. Small molecules, such as calcium ions (Ca 2+ ), are able to move between cells, but large molecules like proteins and DNA cannot fit through the channels. The specificity of the channels ensures that the cells remain independent but can quickly and easily transmit signals. The transfer of signaling molecules communicates the current state of the cell that is directly next to the target cell this allows a group of cells to coordinate their response to a signal that only one of them may have received. In plants, plasmodesmata are ubiquitous, making the entire plant into a giant communication network.

Types of Receptors

Receptors are protein molecules in the target cell or on its surface that bind ligand. There are two types of receptors, internal receptors and cell-surface receptors.

Internal receptors

Internal receptors , also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane. Once inside the cell, many of these molecules bind to proteins that act as regulators of mRNA synthesis (transcription) to mediate gene expression. Gene expression is the cellular process of transforming the information in a cell's DNA into a sequence of amino acids, which ultimately forms a protein. When the ligand binds to the internal receptor, a conformational change is triggered that exposes a DNA-binding site on the protein. The ligand-receptor complex moves into the nucleus, then binds to specific regulatory regions of the chromosomal DNA and promotes the initiation of transcription (Figure 9.4). Transcription is the process of copying the information in a cells DNA into a special form of RNA called messenger RNA (mRNA) the cell uses information in the mRNA (which moves out into the cytoplasm and associates with ribosomes) to link specific amino acids in the correct order, producing a protein. Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or messengers.

Cell-Surface Receptors

Cell-surface receptors , also known as transmembrane receptors, are cell surface, membrane-anchored (integral) proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, in which an extracellular signal is converted into an intracellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.

Because cell-surface receptor proteins are fundamental to normal cell functioning, it should come as no surprise that a malfunction in any one of these proteins could have severe consequences. Errors in the protein structures of certain receptor molecules have been shown to play a role in hypertension (high blood pressure), asthma, heart disease, and cancer.

Each cell-surface receptor has three main components: an external ligand-binding domain, a hydrophobic membrane-spanning region, and an intracellular domain inside the cell. The ligand-binding domain is also called the extracellular domain . The size and extent of each of these domains vary widely, depending on the type of receptor.

EVOLUTION CONNECTION

How Viruses Recognize a Host

Unlike living cells, many viruses do not have a plasma membrane or any of the structures necessary to sustain life. Some viruses are simply composed of an inert protein shell containing DNA or RNA. To reproduce, viruses must invade a living cell, which serves as a host, and then take over the hosts cellular apparatus. But how does a virus recognize its host?

Viruses often bind to cell-surface receptors on the host cell. For example, the virus that causes human influenza (flu) binds specifically to receptors on membranes of cells of the respiratory system. Chemical differences in the cell-surface receptors among hosts mean that a virus that infects a specific species (for example, humans) cannot infect another species (for example, chickens).

However, viruses have very small amounts of DNA or RNA compared to humans, and, as a result, viral reproduction can occur rapidly. Viral reproduction invariably produces errors that can lead to changes in newly produced viruses these changes mean that the viral proteins that interact with cell-surface receptors may evolve in such a way that they can bind to receptors in a new host. Such changes happen randomly and quite often in the reproductive cycle of a virus, but the changes only matter if a virus with new binding properties comes into contact with a suitable host. In the case of influenza, this situation can occur in settings where animals and people are in close contact, such as poultry and swine farms. 1 Once a virus jumps to a new host, it can spread quickly. Scientists watch newly appearing viruses (called emerging viruses) closely in the hope that such monitoring can reduce the likelihood of global viral epidemics.

  1. The virus must infect at least two different animals before infecting humans.
  2. The virus must come into contact with a new host so mutations will occur which allow the virus to bind to that host.
  3. A mutation must occur in the host allowing the virus to bind to the host.
  4. A mutation must occur in the virus allowing the virus to infect a new host, and the virus must come into contact with this host.

Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors, and enzyme-linked receptors.

Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through. To form a channel, this type of cell-surface receptor has an extensive membrane-spanning region. In order to interact with the phospholipid fatty acid tails that form the center of the plasma membrane, many of the amino acids in the membrane-spanning region are hydrophobic in nature. Conversely, the amino acids that line the inside of the channel are hydrophilic to allow for the passage of water or ions. When a ligand binds to the extracellular region of the channel, there is a conformational change in the proteins structure that allows ions such as sodium, calcium, magnesium, and hydrogen to pass through (Figure 9.5).

G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane (Figure 9.6). All G-protein-linked receptors have seven transmembrane domains, but each receptor has its own specific extracellular domain and G-protein-binding site.

Cell signaling using G-protein-linked receptors occurs as a cyclic series of events. Before the ligand binds, the inactive G-protein can bind to a newly revealed site on the receptor specific for its binding. Once the G-protein binds to the receptor, the resultant shape change activates the G-protein, which releases GDP and picks up GTP. The subunits of the G-protein then split into the α subunit and the βγ subunit. One or both of these G-protein fragments may be able to activate other proteins as a result. After awhile, the GTP on the active α subunit of the G-protein is hydrolyzed to GDP and the βγ subunit is deactivated. The subunits reassociate to form the inactive G-protein and the cycle begins anew.

G-protein-linked receptors have been extensively studied and much has been learned about their roles in maintaining health. Bacteria that are pathogenic to humans can release poisons that interrupt specific G-protein-linked receptor function, leading to illnesses such as pertussis, botulism, and cholera. In cholera (Figure 9.7), for example, the water-borne bacterium Vibrio cholerae produces a toxin, choleragen, that binds to cells lining the small intestine. The toxin then enters these intestinal cells, where it modifies a G-protein that controls the opening of a chloride channel and causes it to remain continuously active, resulting in large losses of fluids from the body and potentially fatal dehydration as a result.

Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme. In some cases, the intracellular domain of the receptor itself is an enzyme. Other enzyme-linked receptors have a small intracellular domain that interacts directly with an enzyme. The enzyme-linked receptors normally have large extracellular and intracellular domains, but the membrane-spanning region consists of a single alpha-helical region of the peptide strand. When a ligand binds to the extracellular domain, a signal is transferred through the membrane, activating the enzyme. Activation of the enzyme sets off a chain of events within the cell that eventually leads to a response. One example of this type of enzyme-linked receptor is the tyrosine kinase receptor (Figure 9.8). A kinase is an enzyme that transfers phosphate groups from ATP to another protein. The tyrosine kinase receptor transfers phosphate groups to tyrosine molecules (tyrosine residues). First, signaling molecules bind to the extracellular domain of two nearby tyrosine kinase receptors. The two neighboring receptors then bond together, or dimerize. Phosphates are then added to tyrosine residues on the intracellular domain of the receptors (phosphorylation). The phosphorylated residues can then transmit the signal to the next messenger within the cytoplasm.

VISUAL CONNECTION

  1. dimerization and the downstream cellular response
  2. phosphatase activity, dimerization, and the downstream cellular response
  3. signaling molecule binding, dimerization, and the downstream cellular response
  4. the downstream cellular response

Produced by signaling cells and the subsequent binding to receptors in target cells, ligands act as chemical signals that travel to the target cells to coordinate responses. The types of molecules that serve as ligands are incredibly varied and range from small proteins to small ions like calcium (Ca 2+ ).

Small Hydrophobic Ligands

Small hydrophobic ligands can directly diffuse through the plasma membrane and interact with internal receptors. Important members of this class of ligands are the steroid hormones. Steroids are lipids that have a hydrocarbon skeleton with four fused rings different steroids have different functional groups attached to the carbon skeleton. Steroid hormones include the female sex hormone, estradiol, which is a type of estrogen the male sex hormone, testosterone and cholesterol, which is an important structural component of biological membranes and a precursor of steriod hormones (Figure 9.9). Other hydrophobic hormones include thyroid hormones and vitamin D. In order to be soluble in blood, hydrophobic ligands must bind to carrier proteins while they are being transported through the bloodstream.

Water-Soluble Ligands

Water-soluble ligands are polar and therefore cannot pass through the plasma membrane unaided sometimes, they are too large to pass through the membrane at all. Instead, most water-soluble ligands bind to the extracellular domain of cell-surface receptors. This group of ligands is quite diverse and includes small molecules, peptides, and proteins.

Other Ligands

Nitric oxide (NO) is a gas that also acts as a ligand. It is able to diffuse directly across the plasma membrane, and one of its roles is to interact with receptors in smooth muscle and induce relaxation of the tissue. NO has a very short half-life and therefore only functions over short distances. Nitroglycerin, a treatment for heart disease, acts by triggering the release of NO, which causes blood vessels to dilate (expand), thus restoring blood flow to the heart.


Chemical signaling

There are two kinds of communication in the world of living cells. Communication between cells is called intercellular signaling, and communication within a cell is called intracellular signaling. An easy way to remember the distinction is by understanding the Latin origin of the prefixes: inter- means &ldquobetween&rdquo (for example, intersecting lines are those that cross each other) and intra- means &ldquoinside&rdquo (like intravenous).

Chemical signals are released by signaling cells in the form of small, usually volatile or soluble molecules called ligands. A ligand is a molecule that binds another specific molecule, in some cases, delivering a signal in the process. Ligands can thus be thought of as signaling molecules. Ligands interact with proteins in target cells, which are cells that are affected by chemical signals these proteins are also called receptors. Ligands and receptors exist in several varieties however, a specific ligand will have a specific receptor that typically binds only that ligand.

Forms of Signaling

There are four categories of chemical signaling found in multicellular organisms: paracrine signaling, endocrine signaling, autocrine signaling, and direct signaling across gap junctions (Figure 9.2). The main difference between the different categories of signaling is the distance that the signal travels through the organism to reach the target cell. Not all cells are affected by the same signals.

Figure 9.2. Forms of chemical signaling: autocrine, gap junctions, paracrine, and endocrine.

In chemical signaling, a cell may target itself (autocrine signaling), a cell connected by gap junctions, a nearby cell (paracrine signaling), or a distant cell (endocrine signaling). Paracrine signaling acts on nearby cells, endocrine signaling uses the circulatory system to transport ligands, and autocrine signaling acts on the signaling cell. Signaling via gap junctions involves signaling molecules moving directly between adjacent cells.

Paracrine signaling

Signals that act locally between cells that are close together are called paracrine signals. Paracrine signals move by diffusion through the extracellular matrix. These types of signals usually elicit quick responses that last only a short amount of time. In order to keep the response localized, paracrine ligand molecules are normally quickly degraded by enzymes or removed by neighboring cells. Removing the signals will reestablish the concentration gradient for the signal, allowing them to quickly diffuse through the intracellular space if released again.

One example of paracrine signaling is the transfer of signals across synapses between nerve cells. A nerve cell consists of a cell body, several short, branched extensions called dendrites that receive stimuli, and a long extension called an axon, which transmits signals to other nerve cells or muscle cells. The junction between nerve cells where signal transmission occurs is called a synapse. A synaptic signal is a chemical signal that travels between nerve cells. Signals within the nerve cells are propagated by fast-moving electrical impulses. When these impulses reach the end of the axon, the signal continues on to a dendrite of the next cell by the release of chemical ligands called neurotransmitters by the presynaptic cell (the cell emitting the signal). The neurotransmitters are transported across the very small distances between nerve cells, which are called chemical synapses (Figure 9.3). The small distance between nerve cells allows the signal to travel quickly this enables an immediate response, such as, Take your hand off the stove!

When the neurotransmitter binds the receptor on the surface of the postsynaptic cell, the electrochemical potential of the target cell changes, and the next electrical impulse is launched. The neurotransmitters that are released into the chemical synapse are degraded quickly or get reabsorbed by the presynaptic cell so that the recipient nerve cell can recover quickly and be prepared to respond rapidly to the next synaptic signal.

Figure 9.3. Synapse showing neurotransmitter release.

The distance between the presynaptic cell and the postsynaptic cell&mdashcalled the synaptic gap&mdashis very small and allows for rapid diffusion of the neurotransmitter. Enzymes in the synapatic cleft degrade some types of neurotransmitters to terminate the signal.

Endocrine signaling

Signals from distant cells are called endocrine signals, and they originate from endocrine cells. (In the body, many endocrine cells are located in endocrine glands, such as the thyroid gland, the hypothalamus, and the pituitary gland.) These types of signals usually produce a slower response but have a longer-lasting effect. The ligands released in endocrine signaling are called hormones, signaling molecules that are produced in one part of the body but affect other body regions some distance away.

Hormones travel the large distances between endocrine cells and their target cells via the bloodstream, which is a relatively slow way to move throughout the body. Because of their form of transport, hormones get diluted and are present in low concentrations when they act on their target cells. This is different from paracrine signaling, in which local concentrations of ligands can be very high.

Autocrine signaling

Autocrine signals are produced by signaling cells that can also bind to the ligand that is released. This means the signaling cell and the target cell can be the same or a similar cell (the prefix auto- means self, a reminder that the signaling cell sends a signal to itself). This type of signaling often occurs during the early development of an organism to ensure that cells develop into the correct tissues and take on the proper function. Autocrine signaling also regulates pain sensation and inflammatory responses. Further, if a cell is infected with a virus, the cell can signal itself to undergo programmed cell death, killing the virus in the process. In some cases, neighboring cells of the same type are also influenced by the released ligand. In embryological development, this process of stimulating a group of neighboring cells may help to direct the differentiation of identical cells into the same cell type, thus ensuring the proper developmental outcome.

Direct signaling across gap junctions

Gap junctions in animals and plasmodesmata in plants are connections between the plasma membranes of neighboring cells. These water-filled channels allow small signaling molecules, called intracellular mediators, to diffuse between the two cells. Small molecules, such as calcium ions (Ca2+), are able to move between cells, but large molecules like proteins and DNA cannot fit through the channels. The specificity of the channels ensures that the cells remain independent but can quickly and easily transmit signals. The transfer of signaling molecules communicates the current state of the cell that is directly next to the target cell this allows a group of cells to coordinate their response to a signal that only one of them may have received. In plants, plasmodesmata are ubiquitous, making the entire plant into a giant, communication network.

Types of Receptors

Receptors are protein molecules in the target cell or on its surface that bind ligand. There are two types of receptors, internal receptors and cell-surface receptors.

Internal receptors

Internal receptors, also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane. Once inside the cell, many of these molecules bind to proteins that act as regulators of mRNA synthesis (transcription) to mediate gene expression. Gene expression is the cellular process of transforming the information in a cell&rsquos DNA into a sequence of amino acids, which ultimately forms a protein. When the ligand binds to the internal receptor, a conformational change is triggered that exposes a DNA-binding site on the protein. The ligand-receptor complex moves into the nucleus, then binds to specific regulatory regions of the chromosomal DNA and promotes the initiation of transcription (Figure 9.4). Transcription is the process of copying the information in a cells DNA into a special form of RNA called messenger RNA (mRNA) the cell uses information in the mRNA (which moves out into the cytoplasm and associates with ribosomes) to link specific amino acids in the correct order, producing a protein. Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or messengers.

Figure 9.4. Hydrophobic signaling.

Hydrophobic signaling molecules typically diffuse across the plasma membrane and interact with intracellular receptors in the cytoplasm. Many intracellular receptors are transcription factors that interact with DNA in the nucleus and regulate gene expression.

Cell-surface receptors

Cell-surface receptors, also known as transmembrane receptors, are cell surface, membrane-anchored (integral) proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, in which an extracellular signal is converted into an intercellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.

Because cell-surface receptor proteins are fundamental to normal cell functioning, it should come as no surprise that a malfunction in any one of these proteins could have severe consequences. Errors in the protein structures of certain receptor molecules have been shown to play a role in hypertension (high blood pressure), asthma, heart disease, and cancer.

Each cell-surface receptor has three main components: an external ligand-binding domain, a hydrophobic membrane-spanning region, and an intracellular domain inside the cell. The ligand-binding domain is also called the extracellular domain. The size and extent of each of these domains vary widely, depending on the type of receptor. Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors, and enzyme-linked receptors.

Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through. To form a channel, this type of cell-surface receptor has an extensive membrane-spanning region. In order to interact with the phospholipid fatty acid tails that form the center of the plasma membrane, many of the amino acids in the membrane-spanning region are hydrophobic in nature. Conversely, the amino acids that line the inside of the channel are hydrophilic to allow for the passage of water or ions. When a ligand binds to the extracellular region of the channel, there is a conformational change in the proteins structure that allows ions such as sodium, calcium, magnesium, and hydrogen to pass through (Figure 9.5)

Figure 9.5. A closed gated ion channel. Gated ion channels form a pore through the plasma membrane that opens when the signaling molecule binds. The open pore then allows ions to flow into or out of the cell.

G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane (Figure 9.6). All G-protein-linked receptors have seven transmembrane domains, but each receptor has its own specific extracellular domain and G-protein-binding site.

Cell signaling using G-protein-linked receptors occurs as a cyclic series of events. Before the ligand binds, the inactive G-protein can bind to a newly revealed site on the receptor specific for its binding. Once the G-protein binds to the receptor, the resultant shape change activates the G-protein, which releases GDP and picks up GTP. The subunits of the G-protein then split into the &alpha subunit and the &beta&gamma subunit. One or both of these G-protein fragments may be able to activate other proteins as a result. After awhile, the GTP on the active &alpha subunit of the G-protein is hydrolyzed to GDP and the &beta&gamma subunit is deactivated. The subunits reassociate to form the inactive G-protein and the cycle begins anew.

Figure 9.6. Heterotrimeric G proteins have three subunits: &alpha, &beta, and &gamma. When a signaling molecule binds to a G-protein-coupled receptor in the plasma membrane, a GDP molecule associated with the &alpha subunit is exchanged for GTP. The &beta and &gamma subunits dissociate from the &alpha subunit, and a cellular response is triggered either by the &alpha subunit or the dissociated &beta&gamma pair. Hydrolysis of GTP to GDP terminates the signal.

G-protein-linked receptors have been extensively studied and much has been learned about their roles in maintaining health. Bacteria that are pathogenic to humans can release poisons that interrupt specific G-protein-linked receptor function, leading to illnesses such as pertussis, botulism, and cholera. In cholera (Figure 9.7), for example, the water-borne bacterium Vibrio cholerae produces a toxin, choleragen, that binds to cells lining the small intestine. The toxin then enters these intestinal cells, where it modifies a G-protein that controls the opening of a chloride channel and causes it to remain continuously active, resulting in large losses of fluids from the body and potentially fatal dehydration as a result.

Figure 9.7. Transmitted primarily through contaminated drinking water, cholera is a major cause of death in the developing world and in areas where natural disasters interrupt the availability of clean water. The cholera bacterium, Vibrio cholerae, creates a toxin that modifies G-protein-mediated cell signaling pathways in the intestines. Modern sanitation eliminates the threat of cholera outbreaks, such as the one that swept through New York City in 1866. This poster from that era shows how, at that time, the way that the disease was transmitted was not understood. (credit: New York City Sanitary Commission)

Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme. In some cases, the intracellular domain of the receptor itself is an enzyme. Other enzyme-linked receptors have a small intracellular domain that interacts directly with an enzyme. The enzyme-linked receptors normally have large extracellular and intracellular domains, but the membrane-spanning region consists of a single alpha-helical region of the peptide strand. When a ligand binds to the extracellular domain, a signal is transferred through the membrane, activating the enzyme. Activation of the enzyme sets off a chain of events within the cell that eventually leads to a response. One example of this type of enzyme-linked receptor is the tyrosine kinase receptor (Figure 9.8). A kinase is an enzyme that transfers phosphate groups from ATP to another protein. The tyrosine kinase receptor transfers phosphate groups to tyrosine molecules (tyrosine residues). First, signaling molecules bind to the extracellular domain of two nearby tyrosine kinase receptors. The two neighboring receptors then bond together, or dimerize. Phosphates are then added to tyrosine residues on the intracellular domain of the receptors (phosphorylation). The phosphorylated residues can then transmit the signal to the next messenger within the cytoplasm.

Figure 9.8. A receptor tyrosine kinase is an enzyme-linked receptor with a single transmembrane region, and extracellular and intracellular domains. Binding of a signaling molecule to the extracellular domain causes the receptor to dimerize. Tyrosine residues on the intracellular domain are then autophosphorylated, triggering a downstream cellular response. The signal is terminated by a phosphatase that removes the phosphates from the phosphotyrosine residues.


9.2.1 Signaling Pathways and Signal Amplification

Although signaling molecules are often found at very low concentrations, they may produce profound effects. After the ligand binds to the cell-surface receptor, the activation of the receptor’s intracellular components sets off a chain of events that is called a signaling pathway or a signaling cascade. In a signaling pathway, second messengers, enzymes, and/or activated proteins activate other proteins or messengers (Figure 9.11). Each member of the pathway can activate thousands of the next member of the pathway in a process called signal amplification. Since the signal is amplified at each step, a very large response can be generated from a single receptor binding a ligand.

Figure 9.11 The epidermal growth factor receptor, EGFR, is a receptor tyrosine kinase. Top. When EGF binds to its receptor, two proteins activate RAS, a small G-protein. Bottom. RAS activates RAF, which phosphorylates MEK, which phosphorylates ERK. Activated ERK enters the nucleus and triggers a cell response.

An example of a signaling pathway is shown is Figure 9.11. Epidermal growth factor (EGF) is a signaling molecule that is involved in the regulation of cell growth, wound healing, and tissue repair. The receptor for EGF (EGFR) is a tyrosine kinase. An activated kinase phosphorylates and activates many downstream molecules. When EGF binds to EGFR, a cascade of downstream phosphorylation events signals the cell to grow and divide. If EGFR is activated at inappropriate times, uncontrolled cell growth (cancer) may occur.

In certain cancers, the GTPase activity of the RAS G-protein is inhibited. This means that the RAS protein can no longer hydrolyze GTP into GDP. What effect would this have on downstream cellular events?


Cell Communication

Communication between cells allows them to relay information and regulate the activity of other cells. It also allows a group of cells to coordinate their activities. Cells talk to each other through the language of small molecules. These can be amine, peptides, steroids, nucleotides and gases. Some of these molecules diffuse across the plasma membrane to bind their intracellular targets, but most must interact with a cell surface receptor that then triggers changes in cell activity. The connection between receptor and cellular targets is called signal transduction and usually involves several proteins, small molecules and ions. Cells contain several signal transduction pathways and there is crosstalk between pathways. Pathways can share the same protein, and proteins in separate pathways can affect the activity of each other.

The effects of a signaling molecule can be fast or slow. Fast responses usually involve changes in the activity of proteins (muscle contraction, fusion of secretory vesicles, changes in metabolism), whereas slow responses require synthesis of new proteins. Fast responses are transient and the effects can be rapidly reversed. Slow responses often generate long-term or permanent changes in cell behavior. The same signaling molecule will often elicit a rapid, transient response from a cell followed by a slower, long term change in cell behavior.

Signaling between cells can occur over a variety of distances. Paracrine signaling involves cells in the same location or tissue, and the signaling molecule does not enter the blood stream. Autocrine signaling is a form of paracrine signaling in which the signaling molecule affects the cell that produced it. Endocrine signaling involves cells in separate organs and tissues and requires the blood stream to transport the signaling molecule between organs. Signaling also occurs between cells that are direct physical contact. Interactions between proteins on the surfaces of cells can trigger changes in cell behavior. For example, proteins on the surface of T-cells and antigen presenting cells interact to activate signaling pathways in T-cells. One specialized type of signaling is neurotransmission. Neurons interact with their target cells but utilize small molecules called neurotransmitters to communicate with their target cells.

Signaling pathways can be complex due to the number of components and the crosstalk between different signaling pathways. In addition, signaling pathways are often regulated by positive and negative feedback. Positive feedback can activate signaling pathways that remain active even when the signaling molecule is removed. Negative feedback pathways generate a variety of patterns in cell activity.

Steroids

Steroids are small hydrophobic molecules that can diffuse across the plasma membrane. Steroids interact with receptors inside the cell that alter the transcriptional activity of different genes. Usually, transcription of these genes is inhibited in the absence of the steroid. Often these transcription factors are kept in the cytoplasm in the absence of steroid preventing them from binding to their target genes. Upon binding steroid, the receptors undergo a conformational change that releases and inhibitory protein which in some cases allows them to be imported into the nucleus. Steroid receptors activate the expression of early response genes that encode transcription factors that turn on expression of secondary response genes. The proteins encoded by the secondary response genes usually generate changes in cellular behavior.

Ligand-gated Ion Channels

Some ion channels in the plasma membrane are receptors for signaling molecules. Upon binding the signaling molecule, the ion channels open allowing passage of ions. The flow of ions depolarizes the membrane setting off an action potential. The action potential can move along the surface of the cell, triggering other cellular events. Signaling via ion channels is usually very rapid and is the mechanism by which skeletal muscle is stimulated to contract.

G-Protein Coupled Receptors

Some receptors in the plasma membrane physically interact with heterotrimeric G-proteins that reside on cytoplasmic surface of the plasma membrane. Heterotrimeric G-proteins consist of an alpha subunit (Gα) that binds and hydrolyzes GTP and a beta and a gamma subunits (Gβγ) that inhibit Gα but can also participate in signaling reactions. The receptors are notable because they span the membrane 7 times and contain a guanine nucleotide exchange (GEF) domain. When they bind ligand, the GEF domain catalyzes Gα to bind GTP. Gα-GTP dissociates from the Gβγ and can alter the activity of different downstream enzymes. Some Gα subunits (Gs) activate downstream enzymes while others (Gi) inhibit the activity of downstream enzymes.

Downstream Effectors of Heterotrimeric G-Proteins

Some Gs subunits activate adenylyl cyclase that converts ATP into cAMP. Adenylyl cylclase resides on the cytoplasmic surface of the plasma membrane and can increase the concentration of cAMP 20 fold. Increased cAMP concentrations activate protein kinase A by causing its regulatory subunits to dissociate. Protein kinase A has numerous cellular targets. It affects metabolism by activating enzymes that breakdown glycogen and it alters gene expression by activating transcription factors. In contrast to Gs, some Gi subunits inhibit the activity of adenylyl cyclase. To limit the extent of signaling via cAMP, cells express phosphodiesterase that hydrolyzes cAMP, reducing the activity of protein kinase A.

Other Gs subunits activate phospholipases. Phospholipases cleave a class of lipids called phosphatidylinositols. Gs tend to activate phospholipase C that generates inositol 3-phosphate (IP3) and diacylglycerorl (DAG). IP3 binds to calcium channels in the endoplasmic reticulum causing them to open and release calcium into the cytoplasm. Many cellular events are regulated by calcium levels including muscle contraction. Calcium, with help from DAG, also activates protein kinase C that has numerous cellular targets. DAG can also be converted to arachidonic acid that is used to synthesize prostagladins which are mediators of inflammation and pain.

Receptor Tyrosine Kinases

Some signaling molecules bind receptors that usually span the membrane once. These receptors contain a kinase domain on their cytoplasmic tail. When bound to ligand the kinase domain is activated and the receptors phosphorylate other similar receptors. The phosphorylated tails of the receptors are recognized by a number of different signaling proteins. Receptors activate these signaling proteins by bringing concentrating them near their substrates. Normally, these signaling proteins reside at low concentration in the cytosol and rarely interact with their substrates. By bringing the signaling proteins closer to their substrates, receptor tyrosine kinases greatly increase the signaling reactions. Some of the signaling proteins that bind receptor tyrosine kinases are phospholipases, enzymes that regulate GTP-binding proteins, and phosphatidylinositol kinases.

Phosphatidylinositol kinases phosphorylate phosphatidylinositols and can generate a patch of specific phosphtidylinositol in the inner leaflet of the plasma membrane. Some signaling proteins contain domains that bind specific phosphatidylinositols and become concentrated at the plasma membrane. One of these proteins usually activates the other, and the second protein alters the specific cellular events.

MAP Kinases

The MAP kinase pathway is a series of kinases that phosphorylate one another in an ordered fashion. When activated, the top kinase, MAP-kinase kinase kinase (MAP-KKK), phosphorylates MAP-kinase kinase that then phosphorylates MAP-kinase. Phosphorylated MAP-kinase phosphorylates a variety of cellular targets. Many signaling pathways employ the MAP kinase cascade but one of the most common mechanisms to activate MAP kinases is through Ras. Ras is small GTP-binding proteins that resides at the plasma membrane. Receptor tyrosine kinases can recruit the GEF for Ras that catalyzes its binding of GTP. In the GTP-bound state Ras turns on the activity of MAP-kinase kinase kinase.

There are several different types of proteins that functions as MAP-KKK, MAP-KK or MAP-K and one of the challenges is to keep MAP kinases in one pathway from activating MAP kinases in another pathway. Cells maintain integrity of MAP kinase pathways through the use of scaffolding proteins. Scaffolding proteins bind MAP kinases that participate in the same pathway, thereby decreasing the probability that they will phosphorylate MAP kinases in another pathway.

Turning Off the Signal

As mentioned, cells need to terminate signaling events because prolonged stimulation can cause damage to cells and lead to cell death. Some signaling pathways are inactivated by removing the receptor that activates the pathway from the plasma membrane. Receptor-mediated endocytosis takes up a portion of the plasma membrane in clathrin-coated vesicles. These vesicles can recruit receptors thereby removing them from the plasma membrane. The vesicles fuse with low pH endosomes that usually dissociate the ligand from the receptor, and the receptor can be recycled to the plasma membrane. In some cases, the receptor is permanently removed from the plasma membrane by shuttling the receptor to lysosomes where it is degraded.

Receptors can also be inactivated while remaining in the plasma membrane. Some activated receptors turn on proteins that modify the receptor (phosphorylation). The modified form of the receptor is then bound by inhibitory proteins that prevent the receptor from activating downstream signaling pathways.

In some cases, the signaling molecule is removed from outside the cell. Some cells contain enzymes outside the cell that degrade signaling molecules. In other cases, cells can take up signaling molecules outside the cell by endocytosis.