G protein-coupled receptors are the most abundant class of receptors in the human body. These receptors are exposed at the extracellular surface of the cell membrane, traverse the membrane, and possess intracellular regions that activate a unique class of signaling molecules called G proteins. (G proteins are so named because they bind the guanine nucleotides GTP and GDP.) G protein-coupled signaling mechanisms are involved in many important processes, including vision, olfaction, and neurotransmission.
G protein-coupled receptors all have seven transmembrane regions within a single polypeptide chain. Each transmembrane region consists of a single α helix, and the α helices are arranged in a characteristic structural motif that is similar in all members of this receptor class. The extracellular domain of this class of proteins usually contains the ligand-binding region, although some G protein-coupled receptors bind ligands within the transmembrane domain of the receptor. In the resting (unstimulated) state, the cytoplasmic domain of the receptor is noncovalently linked to a G protein that consists of α and βγ subunits. Upon activation, the α subunit exchanges GDP for GTP. The α-GTP subunit then dissociates from the βγ subunit, and the α or βγ subunit diffuses along the inner leaflet of the plasma membrane to interact with a number of different effectors.

These effectors include adenylyl cyclase, phospholipase C, various ion channels, and other classes of proteins. Signals mediated by G proteins are usually terminated by the hydrolysis of GTP to GDP, which is catalyzed by the inherent GTPase activity of the α subunit .

One major role of the G proteins is to activate the production of second messengers, that is, signaling molecules that convey the input provided by the first messenger—usually an endogenous ligand or an exogenous drug—to cytoplasmic effectors . The activation of cyclases, such as adenylyl cyclase, which catalyzes the production of the second messenger cyclic adenosine-3′,5′-monophosphate (cAMP), and guanylyl cyclase, which catalyzes the production of cyclic guanosine-3′,5′-monophosphate (cGMP), constitutes the most common pathway linked to G proteins. In addition, G proteins can activate the enzyme phospholipase C (PLC) which, among other functions, plays a key role in regulating the concentration of intracellular calcium. Upon activation by a G protein, PLC cleaves the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) to the second messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). IP3 triggers the release of Ca2+ from intracellular stores, thereby dramatically increasing the cytosolic Ca2+ concentration and activating downstream molecular and cellular events. DAG activates protein kinase C, which then mediates other molecular and cellular events, including smooth muscle contraction and transmembrane ion transport. All of these events are dynamically regulated, so that the different steps in the pathways are activated and inactivated with characteristic kinetics.

A large number of Gα protein isoforms have now been identified, each of which has unique effects on its targets. A few of these G proteins include G-stimulatory (Gs), G-inhibitory (Gi), Gq, Go, and G12/13. Examples of the effects of these isoforms are shown in Table 1-4. The differential functioning of these G proteins, some of which may couple in different ways to the same receptor in different cell types, is likely to be important for the potential selectivity of future drugs. The βγ subunits of G proteins can also act as second messenger molecules, although their actions are not as thoroughly characterized.

One important class in the G protein-coupled receptor family is the β-adrenergic receptor group. The most thoroughly studied of these receptors have been designated β1, β2, and β3. As discussed in more detail in Chapter 9, Adrenergic Pharmacology, β1 receptors play a role in controlling heart rate; β2 receptors are involved in the relaxation of smooth muscle; and β3 receptors play a role in the mobilization of energy by fat cells. Each of these receptors is stimulated by the binding of endogenous catecholamines, such as epinephrine and norepinephrine, to the extracellular domain of the receptor. Epinephrine binding induces a conformational change in the receptor, activating G proteins associated with the cytoplasmic domain of the receptor. The activated (GTP-bound) form of the G protein activates adenylyl cyclase, resulting in increased intracellular cAMP levels and downstream cellular effects.

Source of text: David Golan: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition

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