FIGURE 2–10 The guanine nucleotide-dependent activation-inactivation cycle of G proteins. The agonist activates the receptor (R→R*), which promotes release of GDP from the G protein (G), allowing entry of GTP into the nucleotide binding site. In its GTP-bound state (G-GTP), the G protein regulates activity of an effector enzyme or ion channel (E→E*). The signal is terminated by hydrolysis of GTP, followed by return of the system to the basal unstimulated state. Open arrows denote regulatory effects. (Pi, inorganic phosphate.)
TABLE 2–1 G proteins and their receptors and effectors.
cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; IP3, inositol-1,4,5-trisphosphate.
of G proteins. The apparent promiscuity of such a ligand allows it to elicit different G protein-dependent responses in different cells. For instance, the body responds to danger by using catecholamines (norepinephrine and epinephrine) both to increase heart rate and to induce constriction of blood vessels in the skin, by acting on Gs-coupled β adrenoceptors and Gq-coupled α1 adrenoceptors, respectively. Ligand promiscuity also offers opportunities in drug development (see Receptor Classes & Drug Development in the following text).
Receptors that signal via G proteins are often called “G protein-coupled receptors” (GPCRs). GPCRs make up the largest receptor family and are also called “seven-transmembrane” (7TM) or “serpentine” receptors because the receptor polypeptide chain “snakes” across the plasma membrane seven times (Figure 2–11). Receptors for adrenergic amines, serotonin, acetylcholine (muscarinic but not nicotinic), many peptide hormones, odorants, and even visual receptors (in retinal rod and cone cells) all belong to the GPCR family. All were derived from a common evolutionary precursor. A few GPCRs (eg, GABAB and metabotropic glutamate receptors) require stable assembly into homodimers (complexes of two identical receptor polypeptides) or heterodimers (complexes of different isoforms) for functional activity. However, in contrast to tyrosine kinase and cytokine receptors, dimerization is not universally required for GPCR activation, and many GPCRs are thought to function as monomers.
GPCRs can bind agonists in a variety of ways, but they all appear to transduce signals across the plasma membrane in a similar way. Agonist binding (eg, a catecholamine or acetylcholine) stabilizes a conformational state of the receptor in which the cytoplasmic ends of the transmembrane helices spread apart by about 1 nm, opening a cavity in the receptor’s cytoplasmic surface that binds a critical regulatory surface of the G protein. This reduces nucleotide affinity for the G protein, allowing GDP to dissociate and GTP to replace it (this occurs because GTP is normally present in the cytoplasm at much higher concentration than GDP). The GTP-bound form of G protein then dissociates from the receptor and can engage downstream mediators. Thus GPCR–G protein coupling involves coordinated conformational change in both proteins, allowing agonist binding to the receptor to effectively “drive” a nucleotide exchange reaction that “switches” the G protein from its inactive (GDP-bound) to active (GTP-bound) form. Figure 2–11 shows the main components schematically.