Inhibitor Adenylate Cyclase

Transmembrane receptors of various hormones are coupled to adenylate cyclase (AC) via heterotrimeric G-proteins. Ligand binding to the receptor changes the receptor conformation, allowing it to associate with a G-protein. This results in the activation of the specific G-protein via exchange of GTP for GDP bound to the α-subunit of the G-protein. The activated G-protein in turn activates AC resulting in the conversion of ATP to cAMP. cAMP then acts to regulate a wide variety of cellular processes. AC can couple with both the stimulatory and inhibitory G-proteins (G_s and G_i). Interaction with G_s stimulates its activity and interaction with G_i inhibits its enzymatic activity.

At least nine different isoforms of AC have been reported that differ in their regulatory properties and are differentially expressed in various tissues. They are integral membrane proteins that are composed of two cytoplasmic domains and two membrane-spanning domains, each of which contains six transmembrane spans. The amino acid sequence of each cytoplasmic domain, which is thought to contain a nucleotide (ATP) binding site, is well conserved among the various subtypes. Although ACs can exist in both particulate and soluble forms, the particulate form is more prevalent in mammals. Based on the conservation of their catalytic domains, three classes of ACs are described: class I-ACs are found in Gram-negative facultative anaerobes, such as E. coli; class II-"toxic"' ACs, including calmodulin (CaM)-activated ACs are found in pathogenic bacteria, such as Bordetella pertussis and Bacillus anthracis; and class III-ACs are found in a wide variety of organisms ranging from bacteria to human. Class III-AC also include nine isoforms found in mammals, which are designated AC-1 to AC-9. These nine isoforms are stimulated by the a-subunit of G_s-protein and by forskolin. ACs are also capable of receiving signals from a variety of other sources, such as G_i-α, protein kinase A, C, CaM kinase, and Ca²⁺/CaM. Hormonal activation of CaM-dependent adenylate cyclase occurs at very low Ca²⁺ levels. The activity of AC is inhibited by high levels of Ca²⁺, which also activates CaM-dependent phosphodiesterase.

References:
Insel, P.A., and Ostrom, R.S. 2003. Cell. Mol. Neurobiol. 23, 305.
Schwartz, J.H. 2001. Proc. Natl. Acad. Sci. USA 98, 13482.
Sunahara, R.K., et al. 1996. Annu. Rev. Pharmacol. Toxicol. 36, 461.
MacNeil, S., et al. 1985. Cell Calcium 6, 213.
Cui, H., and Green, R. D. 2001. Biochem. Biophys. Res. Comm. 283, 107.