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.

Forskolin-inducible cAMP Pathway Negatively Regulates T-cell Proliferation by Uncoupling the Interleukin-2 Receptor Complex

“…Early events in T-cell activation require the intracellular accumulation of calcium to activate key signaling pathways. Human T-cells and lymphoid cell lines, including MT-2 and Kit 225 cells, express AC III 3 known to be activated by calcium (55). Similarly, other groups have shown that high avidity TCR engagement inhibits T-cell proliferation by blocking activation of Stat5, Jak1, and Jak3 mediated by IL-2 or IL-4 (25).…”

Serum Amyloid A3 Secreted by Preosteoclasts Inhibits Parathyroid Hormone-stimulated cAMP Signaling in Murine Osteoblasts

“…FSK acts independently of receptors to directly activate all adenylyl cyclases (ACs) except AC 9 (21,22). We found that FSK-stimulated Ramp3 expression was inhibited by WT, but not Cox2 KO, CM (Fig.…”

Scaffolding by A-Kinase Anchoring Protein Enhances Functional Coupling between Adenylyl Cyclase and TRPV1 Channel

“…RT-PCR analysis and opioid inhibition of cAMP in DRGs suggest the presence of all AC isoforms except AC2 and AC7 (48). Knock-out studies of AC isoforms implicate both AC1 and AC5 in pain pathways.…”