Physiological roles for G protein-regulated adenylyl cyclase isoforms: insights from knockout and overexpression studies

Abstract

Cyclic AMP is a universal second messenger, produced by a family of adenylyl cyclase (AC) enzymes. The last three decades have brought a wealth of new information about the regulation of cyclic AMP production by ACs. Nine hormone-sensitive, membrane-bound AC isoforms have been identified in addition to a tenth isoform that lacks membrane spans and more closely resembles the cyanobacterial AC enzymes. New model systems for purifying and characterizing the catalytic domains of AC have led to the crystal structure of these domains and the mapping of numerous interaction sites. However, big hurdles remain in unraveling the roles of individual AC isoforms and their regulation in physiological systems. In this review we explore the latest on AC knockout and overexpression studies to better understand the roles of G protein regulation of ACs in the brain, olfactory bulb, and heart.

Fig. 1.

Structure of adenylyl cyclase. a Crystal structure of cytoplasmic domains of AC in complex with GTPγ S-Gα, forskolin (FSK) and P-site inhibitor, 2′ 5′ -dideoxy-3′ ATP [100] . Shown are C1 (yellow), C2 (rust), Gs α (green), FSK (cyan), and P-site inhibitor (dark blue). Membrane spans are modeled from the 12-membrane spanning transporters [199] . b Alternate view from cytoplasmic side, showing forskolin and catalytic site more clearly. Interaction site of Giα with C1 domain is indicated by an arrow.