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Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000.

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Molecular Cell Biology. 4th edition.

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Section 20.3G Protein –Coupled Receptors and Their Effectors

Many different mammalian cell-surface receptors are coupled to a trimeric signal-transducing G protein. As noted earlier, ligand binding to these receptors activates their associated G protein, which then activates an effector enzyme to generate an intracellular second messenger (see Figure 20-3a). All G protein – coupled receptors (GPCRs) contain seven membrane-spanning regions with their N-terminal segment on the exoplasmic face and their C-terminal segment on the cytosolic face of the plasma membrane (Figure 20-10). This large receptor family includes light-activated receptors (rhodopsins) in the eye and literally thousands of odorant receptors in the mammalian nose (Section 21.6), as well as numerous receptors for various hormones and neurotransmitters (Section 21.5). Although these receptors are activated by different ligands and may mediate different cellular responses, they all mediate a similar signaling pathway (see Figure 20-6).

Figure 20-10. Schematic diagram of the general structure of G protein – linked receptors.

Figure 20-10

Schematic diagram of the general structure of G protein – linked receptors. All receptors of this type contain seven transmembrane α-helical regions. The loop between (more...)

To illustrate the operation of this important class of receptors, we discuss the structure and function of the catecholamine receptors that bind epinephrine and norepinephrine and of their associated signal-transducing G proteins. In this receptor system, we focus on the effector enzyme adenylyl cyclase, which synthesizes the second messenger cAMP. Later we describe how other receptors and other G proteins allow cells to integrate the actions of different types of receptors, to modify other enzymes, to control essential metabolic processes, and to alter gene expression.

Binding of Epinephrine to Adrenergic Receptors Induces Tissue-Specific Responses

Epinephrine and norepinephrine were originally recognized as products of the medulla, or core, of the adrenal gland and are also known as adrenaline and noradrenaline. Embryologically, nerve cells derive from the same tissue as adrenal medulla cells, and norepinephrine is also secreted by differentiated nerve cells. Both hormones are charged compounds that belong to the catecholamines, active amines containing a catechol moiety:

Image ch20e9.jpg
Epinephrine, which binds to two types of GPCRs, is particularly important in mediating the body’s response to stress, such as fright or heavy exercise, when all tissues have an increased need for glucose and fatty acids. These principal metabolic fuels can be supplied to the blood in seconds by the rapid breakdown of glycogen in the liver (glycogen-olysis) and of triacylglycerol in the adipose storage cells (lipolysis).

In mammals, the liberation of glucose and fatty acids can be triggered by binding of epinephrine (or norepinephrine) to β-adrenergic receptors on the surface of hepatic (liver) and adipose cells. Epinephrine bound to similar β-adrenergic receptors on heart muscle cells increases the contraction rate, which increases the blood supply to the tissues. Epinephrine bound to β-adrenergic receptors on smooth muscle cells of the intestine causes them to relax. Another type of epinephrine receptor, the α2-adrenergic receptor, is found on smooth muscle cells lining the blood vessels in the intestinal tract, skin, and kidneys. Epinephrine bound to α2 receptors causes the arteries to constrict, cutting off circulation to these peripheral organs. These diverse effects of epinephrine are directed to a common end: supplying energy for the rapid movement of major locomotor muscles in response to bodily stress. As discussed in more detail later, β- and α-adrenergic receptors are coupled to different G proteins. Both β1- and β2-adrenergic receptors are coupled to G proteins (Gs), which activate adenylyl cyclase. In contrast, α1 and α2 receptors are coupled to two other G proteins, Gq and Gi, respectively. Gi inhibits adenylyl cyclase, and Gq stimulates phospholipase C to generate IP3 and DAG as second messengers.

Stimulation of β-Adrenergic Receptors Leads to a Rise in cAMP

Many of the very different tissue-specific responses induced by binding of epinephrine to β-adrenergic receptors are mediated by a rise in the intracellular level of cAMP, resulting from activation of adenylyl cyclase. As a second messenger, cAMP acts to modify the rates of different enzyme-catalyzed reactions in specific tissues generating various metabolic responses. Binding of numerous other hormones to their receptors also leads to a rise in intracellular cAMP and characteristic tissue-specific metabolic responses (see later section).

Several types of experiments have been used to establish that binding of epinephrine to the β-adrenergic receptor induces a rise in cAMP. The data in Figure 20-11 show that the KD for binding of epinephrine and other catecholamines to cell-surface β-adrenergic receptors is about the same as the ligand concentration that induces a half-maximal activation of adenylyl cyclase. The experiment depicted in Figure 20-12 with purified receptors provided further evidence that the β-adrenergic receptor mediates induction of epinephrine-initiated cAMP synthesis. The same conclusion was reached from studies in which cloned cDNA encoding the β-adrenergic receptor was transfected into receptor-negative cells; the transfected cells acquired the ability to activate adenylyl cyclase in response to epinephrine.

Figure 20-11. Comparison of the abilities of three catecholamines to activate adenylyl cyclase, which catalyzes synthesis of cAMP, and to bind to cell-surface β-adrenergic receptors.

Figure 20-11

Comparison of the abilities of three catecholamines to activate adenylyl cyclase, which catalyzes synthesis of cAMP, and to bind to cell-surface β-adrenergic receptors. The curves (more...)

Figure 20-12. Experimental demonstration that β-adrenergic receptors mediate the induction of epinephrine-initiated cAMP synthesis.

Figure 20-12

Experimental demonstration that β-adrenergic receptors mediate the induction of epinephrine-initiated cAMP synthesis. Target cells lacking any receptors for epinephrine but expressing (more...)

Critical Features of Catecholamines and Their Receptors Have Been Identified

A variety of experimental approaches have provided information about which parts of catecholamine molecules and their receptors are essential for ligand binding and the subsequent activation of adenylyl cyclase. In many of these studies, chemically synthesized analogs of epinephrine have proved useful. These analogs fall into two classes: agonists, which mimic the function of a hormone by binding to its receptor and causing the normal response, and antagonists, which bind to the receptor but do not activate hormoneinduced effects. An antagonist acts as an inhibitor of the natural hormone (or agonist) by competing for binding sites on the receptor, thereby blocking the physiological activity of the hormone.

Comparisons of the molecular structure and activity of various catecholamine analogs indicate that the side chain containing the NH group determines the affinity of the ligand for the receptor, while the catechol ring is required for the ligand-induced increase in cAMP level (Table 20-2). As is true for epinephrine, the KD for binding of an agonist, such as isoproterenol, to β-adrenergic receptors generally is the same as the concentration required for half-maximal elevation of cAMP (see Figure 20-11). This relationship indicates that activation of adenylyl cyclase by isoproterenol is proportional to the number of β-adrenergic receptors filled with this agonist. Interestingly, the KD for binding of isoproterenol to β-adrenergic receptors and subsequent induction of cAMP synthesis is about 10 times lower than the KD for epinephrine; other agonists are even more potent having still lower KD values. The affinity of various antagonists for the β-adrenergic receptor also varies over a wide range.

Table 20-2. Structure of Typical Agonists and Antagonists of the β-Adrenergic Receptor.

Table 20-2

Structure of Typical Agonists and Antagonists of the β-Adrenergic Receptor.

Image med.jpgHumans possess two types of β-adrenergic receptors that are located on different cell types and differ in their relative affinities for various cate-cholamines. Cardiac muscle cells possess β1 receptors, which promote increased heart rate and contractility by binding catecholamines with the rank order of affinities isoproterenol > norepinephrine > epinephrine. Drugs such as practolol, which are used to slow heart contractions in the treatment of cardiac arrhythmia and angina, are β1-selective antagonists (see Table 20-2). These so-called beta blockers usually have little effect on β-adrenergic receptors on other cell types. The smooth muscle cells lining the bronchial passages possess β2 receptors, which mediate relaxation by binding catecholamines with the rank order of affinities isoproterenol >> epinephrine = norepinephrine. Agonists selective for β2 receptors, such as terbutaline, are used in the treatment of asthma because they specifically mediate opening of the bronchioles, the small airways in the lungs.

Although all GPCRs are thought to span the membrane seven times and hence to have similar three-dimensional structures, their amino acid sequences generally are quite dissimilar. For example, the sequences of the closely related β1- and β2-adrenergic receptors are only 50 percent identical; the sequences of the α- and β-adrenergic receptors exhibit even less homology. The specific amino acid sequence of each receptor determines which ligands it binds and which G proteins interact with it.

Studies with mutant forms of the β-adrenergic receptor generated by site-specific mutagenesis have identified four residues, located in transmembrane helices 3, 5, and 6, that participate in binding the agonist isoproterenol (Figure 20-13). Mutation of any one of these residues significantly reduces the ability of the receptor to bind the agonist. Binding of ligand to a β-adrenergic receptor is thought to cause several of the helices, particularly helices 5 and 6, to move relative to each other. As a result, the conformation of the long cytosolic loop connecting these two helices changes in a way that allows this loop to bind and activate the transducing G protein. The role of this hydrophilic loop in determining a receptor’s specificity for a particular G protein was demonstrated in studies with recombinant chimeric receptor proteins containing part of an α2 receptor and part of a β2 receptor (Figure 20-14). It is thought that specific regions within the loop assume a unique three-dimensional structure in all receptors that bind the same G protein (e.g., Gs or Gi). Regions of the loop joining helices 3 and 4 in other GPCRs contribute to G protein binding. The chimeric studies also showed that helix 7 functions in determining ligand specificity. This finding and the results with mutant β2 receptors (see Figure 20-13) suggest that residues in at least four transmembrane helices in GPCRs participate in ligand binding.

Figure 20-13. Model of complex formed between isoproterenol and the β2-adrenergic receptor based on studies with mutant receptors expressed in cultured cells.

Figure 20-13

Model of complex formed between isoproterenol and the β2-adrenergic receptor based on studies with mutant receptors expressed in cultured cells. The polypeptide backbone of the (more...)

Figure 20-14. Demonstration of functional domains in G protein – coupled receptors by experiments with chimeric proteins containing portions of the β2- and α2-adrenergic receptors.

Figure 20-14

Demonstration of functional domains in G protein – coupled receptors by experiments with chimeric proteins containing portions of the (more...)

Trimeric Gs Protein Links β-Adrenergic Receptors and Adenylyl Cyclase

Having described which parts of GPCRs are necessary for interacting with ligand and their associated G protein, we now explain how G proteins function in signal transduction. Again, we focus our attention on β-adrenergic receptors, which are coupled to Gs, or stimulatory G protein. As noted above, the initial response following binding of epinephrine to β-adrenergic receptors is an elevation in the intracellular level of cAMP. The increase in cAMP results from activation of adenylyl cyclase, which converts ATP to cAMP and pyrophosphate (PPi). This membrane-bound enzyme has two catalytic domains on the cytosolic face of the plasma membrane that can bind ATP in the cytosol (Figure 20-15). The link between hormone binding to an exterior domain of the receptor and activation of adenylyl cyclase is provided by Gs, which functions as a signal transducer.

Figure 20-15. Schematic diagram of mammalian adenylyl cyclases.

Figure 20-15

Schematic diagram of mammalian adenylyl cyclases. The membrane-bound enzyme contains two similar catalytic domains on the cytosolic face of the membrane and two integral membrane domains, (more...)

Cycling of Gsbetween Active and Inactive Forms

The G proteins that transduce signals from the β-adrenergic receptor and other GPCRs contain three subunits designated α, β, and γ. As explained earlier, these GTPase switch proteins alternate between an “on” state with bound GTP and an “off” state with bound GDP (see Figure 20-5a). For example, when no ligand is bound to a β-adrenergic receptor, the α subunit of Gs protein (G) is bound to GDP and complexed with the β and γ subunits (Figure 20-16). Binding of a hormone or agonist to the receptor changes its conformation, causing it to bind to the trimeric Gs protein in such a way that GDP is displaced from G and GTP is bound. The G·GTP complex, which dissociates from the G complex, then binds to and activates adenylyl cyclase. This activation is short-lived, however, because GTP bound to G hydrolyzes to GDP in seconds, leading to the association of G with G and inactivation of adenylyl cyclase. The G subunit thus relays the conformational change in the receptor triggered by hormone binding to adenylyl cyclase.

Figure 20-16. Activation of adenylyl cyclase following binding of an appropriate hormone (e.g., epinephrine, glucagon) to a Gs protein – coupled receptor.

Figure 20-16

Activation of adenylyl cyclase following binding of an appropriate hormone (e.g., epinephrine, glucagon) to a Gs protein – coupled (more...)

Important evidence supporting this model has come from studies with a nonhydrolyzable analog of GTP called GMPPNP, in which a P – NH – P replaces the terminal phosphodiester bond in GTP:

Image ch20e10.jpg

Although this analog cannot be hydrolyzed, it binds to G as well as GTP does. The addition of GMPPNP and an agonist to an erythrocyte membrane preparation results in a much larger and longer-lived activation of adenylyl cyclase than occurs with an agonist and GTP. Once the GDP bound to G is displaced by GMPPNP, it remains permanently bound to G. Because the G · GMPPNP complex is as functional as the normal G · GTP complex in activating adenylyl cyclase, the enzyme is in a permanently active state.

Amplification of Hormone Signal

The cellular responses triggered by cAMP may require tens of thousands or even millions of cAMP molecules per cell. Thus the hormone signal must be amplified in order to generate sufficient second messenger from the few thousand β-adrenergic receptors present on a cell. Amplification is possible because both receptors and Gs proteins can diffuse rapidly in the plasma membrane. A single receptor-hormone complex causes conversion of up to 100 inactive Gs molecules to the active form. Each active G · GTP, in turn, probably activates a single adenylyl cyclase molecule, which then catalyzes synthesis of many cAMP molecules during the time Gs · GTP is bound to it. Although the exact extent of this amplification is difficult to measure, binding of a single hormone molecule to one receptor molecule can result in the synthesis of at least several hundred cAMP molecules per receptor-hormone complex before the complex dissociates and activation of adenylyl cyclase ceases.

Termination of Cellular Response

Successful cell-to-cell signaling also requires that the response of target cells to a hormone terminate rapidly once the concentration of circulating hormone decreases. Termination of the response to hormones recognized by β-adrenergic receptors is facilitated by a decrease in the affinity of the receptor that occurs when Gs is converted from the inactive to active form. When the GDP bound to G is replaced with a GTP following hormone binding, the KD of the receptor-hormone complex increases, shifting the equilibrium toward dissociation. The GTP bound to G is quickly hydrolyzed, reversing the activation of adenylyl cyclase and terminating the cellular response unless the concentration of hormone remains high enough to form new receptor-hormone complexes. Thus, the continuous presence of hormone is required for continuous activation of adenylyl cyclase. We discuss signal termination in more detail later in this chapter.

Some Bacterial Toxins Irreversibly Modify G Proteins

So far we have discussed the stimulatory G protein (Gs) that links β-adrenergic receptors and some other GPCRs to adenylyl cyclase. Cells, however, contain a number of other trimeric signal-transducing G proteins, including the inhibitory Gi coupled to α-adrenergic receptors. Studies with several bacterial toxins initially helped to unravel the functions of the various G proteins.

Image med.jpgThe cholera toxin is a hexameric protein (containing 1 α subunit and 5 β subunits) produced by the bacterium Vibrio cholerae, the bacterium thatcauses cholera. The classic symptom of cholera is massive diarrhea, caused by water flow from the blood through intestinal epithelial cells into the lumen of the intestine; death from dehydration is common. The α subunit of cholera toxin is an enzyme that penetrates the plasma membrane and enters the cytosol, where it catalyzes the covalent addition of the ADP-ribose moiety from intracellular NAD+ to G. ADP-ribosylated G · GTP can activate adenylyl cyclase normally but cannot hydrolyze the bound GTP to GDP; thus G remains in the active on state, continuously activating adenylyl cyclase (Figure 20-17). As a result, the level of cAMP in the cytosol rises 100-fold or more. In intestinal epithelial cells, this rise apparently causes certain membrane proteins to permit a massive flow of water from the blood into the intestinal lumen. The studies with cholera toxin provided additional confirmation of the cycling of Gs described earlier.

Figure 20-17. Effect of cholera toxin on cycling of Gsα between the active and inactive forms.

Figure 20-17

Effect of cholera toxin on cycling of G between the active and inactive forms. Normally, GTP in the active G · GTP is rapidly hydrolyzed (blue arrow), so that the activation (more...)

Pertussis toxin is secreted by Bordetella pertussis, the bacterium causing whooping cough. The S1 subunit of this toxin catalyzes addition of ADP-ribose to the α subunit of Gi. This irreversible modification prevents release of GDP, locking G in the GDP-bound state. The identification and function of several other G proteins is discussed in later sections.

Adenylyl Cyclase Is Stimulated and Inhibited by Different Receptor-Ligand Complexes

The versatile trimeric G proteins enable different receptor-hormone complexes to modulate the activity of the same effector protein. In many types of cells, for example, binding of different hormones to their respective receptors induces activation of adenylyl cyclase. In the liver, glucagon and epinephrine bind to different GPCRs, but binding of both hormones activates adenylyl cyclase and thus triggers the same metabolic responses. Both types of receptors interact with and activate Gs, converting the inactive Gs · GDP to the active G · GTP form. Activation of adenylyl cyclase, and thus the cAMP level, is proportional to the total concentration of G · GTP resulting from binding of both hormones to their respective receptors.

In some cells, the cAMP level can be both up-regulated and down-regulated by the action of different hormones. In adipose cells, for example, epinephrine, glucagon, and ACTH all stimulate adenylyl cyclase, whereas prostaglandin PGE1 and adenosine inhibit the enzyme. The receptors for PGE1 and adenosine interact with inhibitory Gi, which contains the same β and γ subunits as stimulatory Gs but a different α subunit (G). In response to binding of an inhibitory ligand to its receptor, the associated Gi protein releases its bound GDP and binds GTP; the active G · GTP complex then dissociates from Gβγ and inhibits (rather than stimulates) adenylyl cyclase (Figure 20-18). As discussed later, Gβγ also can directly inhibit the activity of some isoforms of adenylyl cyclase.

Figure 20-18. Hormone-induced activation and inhibition of adenylyl cyclase is mediated by Gsα (blue) and Giα (brown), respectively.

Figure 20-18

Hormone-induced activation and inhibition of adenylyl cyclase is mediated by G (blue) and G (brown), respectively. Binding of G · GTP to adenylyl (more...)

GTP-Induced Changes in G Favor Its Dissociation from Gβγ and Association with Adenylyl Cyclase

Recent x-ray crystallographic studies have revealed how the G protein subunits interact with each other and with an activated receptor and adenylyl cyclase. These structural studies provide clues about how binding of GTP leads to dissociation of Gα from Gβγ, how Gα associates with adenylyl cyclase, and how G and G differ such that one activates adenylyl cyclase and the other inhibits it.

The three-dimensional structure of a trimeric G protein bound to GDP is shown in Figure 20-19. Two surfaces of the α subunit (Gα) interact with Gβ: an N-terminal region near the membrane surface and two adjacent regions called switch I and switch II. Although Gβ and Gγ also contact each other, Gγ does not contact Gα. Ligand binding to a GPCR causes the transmembrane helices in the receptor to slide relative to one another, revealing binding sites in the cytosolic extensions of these helices for the coupled trimeric G protein. Mutagenesis studies have shown that the N- and C-terminal domains of Gα interact with the receptor. X-ray crystallographic studies suggest that these regions of Gα form a continuous surface with the lipid anchors at the C-terminus of Gγ and the N-terminus of Gα. The interactions promote the release of GDP from Gα and the subsequent binding of GTP. Upon binding GTP, Gα undergoes extensive conformational changes in three switch regions. These conformational changes, particularly those within switch I and II, disrupt the molecular interactions between Gα and Gβγ, leading to their dissociation. The separated Gα · GTP and Gβγ then drift apart from one another, anchored to the lipid bilayer, in search of effector proteins.

Figure 20-19. The structure of a trimeric G protein bound to GDP based on x-ray crystallographic analysis.

Figure 20-19

The structure of a trimeric G protein bound to GDP based on x-ray crystallographic analysis. The N-terminus of the α subunit (green) and the C-terminus of the γ subunit (red) (more...)

An understanding of how G · GTP interacts with adenylyl cyclase has come from x-ray crystallographic analysis of the complex between G · GTP and the catalytic domains of adenylyl cyclase. As noted earlier, adenylyl cyclase is a multipass transmembrane protein with two large cytosolic loops containing the catalytic domains (see Figure 20-15). Because such transmembrane proteins are notoriously difficult to crystallize, scientists prepared two protein fragments encompassing the catalytic domains of adenylyl cyclase and allowed them to associate in the presence of G · GTP and forskolin, an agonist of adenylyl cyclase that stabilizes the catalytic fragments in their active conformations. The complex that formed was catalytically active and showed pharmacological and biochemical features similar to those of intact full-length adenylyl cyclase. In this complex, two regions of G · GTP contact the adenylyl cyclase fragments (Figure 20-20). These include the switch II helix and the α3-β5 loop. Hence, the GTP-induced conformation of G that favors its dissociation from Gβγ is precisely the conformation essential for binding of G to adenylyl cyclase.

Figure 20-20. The structure of Gsα · GTP complexed with two fragments encompassing the catalytic domain of adenylyl cyclase.

Figure 20-20

The structure of G · GTP complexed with two fragments encompassing the catalytic domain of adenylyl cyclase. The α3-β5 loop and the helix in the switch II (more...)

To understand how binding of G · GTP promotes adenylyl cyclase activity, scientists will first have to solve the structure of the adenylyl cyclase catalytic domains in their unactivated conformations (i.e., in the absence of bound G · GTP). One hypothesis is that binding of the switch II helix to a cleft in one catalytic domain of adenylyl cyclase leads to rotation of the other catalytic domain. This rotation is proposed to lead to a stabilization of the transition state, thereby stimulating catalytic activity.

Hydrolysis of GTP by the intrinsic GTPase activity of G induces a conformational change that promotes its dissociation from adenylyl cyclase, leading to termination of the signal and reassociation of G with Gβγ. Thus the GTPase activity of G acts as a timer to control the length of time that it is associated with the effector.

G and G Interact with Different Regions of Adenylyl Cyclase

Comparison of the structures of G · GTP and G · GTP suggests a molecular basis for the different effects of Gs and Gi on adenylyl cyclase. Although the overall conformation of the switch II and α3-β5 loops are similar in G · GTP and G · GTP, the relative position of these two regions differs in the two subunits. In G · GTP, these regions are so positioned that they can bind simultaneously to a specific surface in adenylyl cyclase (see Figure 20-20). In G · GTP, however, these two regions are displaced from each other in such a way that they cannot simultaneously bind to this surface of adenylyl cyclase.

The crystal structure of the complex between G · GTP and the adenylyl cyclase catalytic fragments has not been determined, but site-directed mutagenesis studies have identified sequences in both proteins that interact with each other. These studies indicate that the switch II region and probably the α4-α6 loop, but not the α3-α5 loop, in G interact with adenylyl cyclase. Based on these and other studies, investigators have proposed that G interacts with a site directly opposite the G-binding surface of adenylyl cyclase (see Figure 20-20); binding of G to this site is thought to induce a conformational change in the active site that inhibits catalytic activity. As with G, the GTPase activity of G rapidly hydrolyzes its bound GTP, thus terminating the inhibitory signal.

As discussed later, Gβγ also regulates the activity of some adenylyl cyclase isoforms. Genetic studies suggest that the surface of adenylyl cyclase critical for binding of Gβγ is distinct from the surfaces involved in binding of Gi and Gs.

Degradation of cAMP Also Is Regulated

The level of cAMP usually is controlled by the hormoneinduced activation of adenylyl cyclase. Another point of regulation is the hydrolysis of cAMP to 5′-AMP by cAMP phosphodiesterase. This hydrolysis terminates the effect of hormone stimulation. As discussed later, the activity of many cAMP phosphodiesterases is stimulated by an increase in cytosolic Ca2+ (another intracellular second messenger), which often is induced by neuron or hormone stimulation. Some cells also modulate the level of cAMP by secreting it into the extracellular medium.

The synthesis and degradation of cAMP are both subject to complex regulation by multiple hormones, which allows the cell to integrate responses to many types of changes in its internal and external environments.

SUMMARY

  •  Many cell-surface receptors are linked to trimeric G proteins. Ligand binding to these receptors, which contain seven transmembrane domains, leads to activation of an associated signal-transducing G protein.
  •  All G proteins contain three subunits: α, β, and γ. Prior to activation, the α subunit is bound to GDP (see Figure 20-19). Binding of a trimeric G protein to an activated receptor leads to dissociation of GDP, binding of GTP to Gα, and dissociation of Gα · GTP from Gβγ. Gα · GTP and Gβγ can specifically interact with effector proteins leading to changes in their activity (see Figure 20-16).
  •  The intrinsic GTPase activity of Gα inactivates Gα · GTP by catalyzing GTP hydrolysis: Pi is released and the resulting Gα · GDP then dissociates from its effector and reassociates with Gβγ.
  •  Binding of ligand to a G protein – coupled receptor causes a conformational change that permits the receptor to bind to a specific G protein. The long cytosolic loop between helices 5 and 6 in a receptor determines which G protein it binds (see Figure 20-14).
  •  Adenylyl cyclase, which catalyzes the formation of cAMP from ATP, is the best-characterized effector regulated by trimeric G proteins. All adenylyl cyclase isoforms are stimulated by G, but only specific isoforms are inhibited by G and Gβγ. G, G, and Gβγ interact with different regions of the catalytic domain of adenylyl cyclase.

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Copyright © 2000, W. H. Freeman and Company.
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