Recent Advance in Isoform-Specific Regulation of Adenylyl Cyclase

David      Wei-Kang Ho; Masanari      Umemura; Claudio      Bravo; Kousaku      Iwatsubo

Abstract

Cyclic AMP is an ubiquitous molecule that serves as an important second messenger for multiple signaling pathways. At least nine membrane-bound mammalian isoforms of adenylyl cyclase have been identified, and each isoform has a distinct pattern of tissue distribution as well as interaction with regulatory proteins within local cytosolic environment. Adenylyl cyclase is coupled to G-protein receptors and serves to convert ATP to cAMP. Although many of the upstream G-protein receptors and cAMP regulators such as phosphodiesterase have been utilized as targets of pharmacotherapy, the attempt of pharmacologic regulation of adenylyl cyclase itself has not been successful. Recent studies have characterized the distinct physiologic effect of each adenylyl cyclase isoform within different organ systems, suggesting the potential therapeutic utility of isoform-specific regulators of adenylyl cyclase. In the current review, we aim to discuss the effects of genetic regulation for each adenylyl cyclase isoform as well as the development of isoformspecific adenylyl cyclase regulators including their therapeutic potential.

Keywords: cAMP, adenylyl cyclase, P-site inhibitor, forskolin, phosphodiesterase, protein kinase A, G-protein coupled receptor, Epac, adenosine triphosphate, memory loss