Adenylyl Cyclase
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p511-512
2025-12-01
29
Different peptide hormones can either stimulate (s) or inhibit (i) the production of cAMP from adenylyl cyclase through the action of the G-proteins. G-proteins are encoded by at least 10 different genes (Table 1). Two parallel systems, a stimulatory (s) one and an inhibitory (i) one, converge on a catalytic molecule (C). Each consists of a receptor, Rs or Ri , and a regulatory G-protein complex termed Gs and Gi . Both Gs and Gi are heterotrimeric G-proteins composed of α, β, and γ subunits. Since the α subunit in Gs differs from that in Gi , the proteins, which are distinct gene products, are designated αs and αi . The α subunits bind guanine nucleotides. The β and γ subunits are likely always associated (βγ) and appear to function predominantly as a heterodimer. The binding of a hormone to Rs or Ri results in a receptor-mediated activation of G-protein, which entails the exchange of GDP by GTP on α and the concomitant dissociation of βγ from α.
Table1. Classes & Functions of Selected G-Proteins a
The αs protein has intrinsic GTPase activity. The active form, αs-GTP, is inactivated on hydrolysis of the GTP to GDP; the trimeric Gs complex (αβγ) is then reformed and is ready for another cycle of activation. Cholera and pertussis toxins catalyze the ADP ribosylation of αs and αi−2 (see Table 1), respectively. In the case of αs , this modification disrupts the intrinsic GTPase activity; thus, αs cannot reassociate with βγ and is therefore irreversibly activated. ADP ribosylation of αi−2 prevents the dissociation of αi−2 from βγ, and free αi−2 thus cannot be formed. αs activity in such cells is therefore unopposed.
There is a large family of G-proteins, and these are part of the superfamily of GTPases. The G-protein family is classified according to sequence homology into four subfamilies, as illustrated in Table 1. There are 21 α, 5 β, and 8 γ subunit genes. Various combinations of these subunits provide a large number of possible αβγ complexes.
The α subunits and the βγ complex have actions independent of those on adenylyl cyclase (see Figure 1 and Table 1). Some forms of αi stimulate K+ channels and inhibit Ca2+ channels, and some αs molecules have the opposite effects. Members of the Gq family activate the phospholipase C group of enzymes. The βγ complexes have been associated with K+ channel stimulation and phospholipase C activation. G proteins are involved in many important biologic processes in addition to hormone action. Notable examples include olfaction (αOLF ) and vision (αt ). Some examples are listed in Table 1. GPCRs are implicated in a number of diseases and are major targets for pharmaceutical agents.
Fig1. Components of the hormone receptor–G-protein effector system. Receptors that couple to effectors through G-proteins, the G-protein–coupled receptors (GPCRs), typically have seven α-helical membrane-spanning domains (here shown as long cylinders). In the absence of hormone (left), the heterotrimeric G-protein complex (α,β,γ) is in an inactive guanosine diphosphate (GDP)-bound form and is probably not associated with the receptor. This complex is anchored to the plasma membrane through prenylated groups on the βγ subunits (wavy lines) and perhaps by myristoylated groups on α subunits (not shown). On binding of hormone (H) to the receptor, there are conforma tional changes within the receptor (as indicated by the tilted membrane-spanning domains) and association of the G-protein complex with the rearranged receptor—this then activates the G-protein complex. This activation results from the exchange of GDP with guanosine triphosphate (GTP) on the α subunit, after which α and βγ dissociate. The α subunit binds to and activates the effector (E). E can be adenylyl cyclase, Ca2+, Na+, or Cl− channels (αs ), or it could be a K+ channel (αi ), phospholipase Cβ (αq ), or cGMP phosphodiesterase (αt ); see Table 1. The βγ subunit can also have direct actions on E. (Reproduced with permission from Becker KL: Principles and Practice of Endocrinology and Metabolism, 3rd ed. Philadelphia, PA: Lippincott; 2001.)
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