Abstract
Cyclic adenosine monophosphate (cAMP), synthesized by adenylyl cyclase (AC), is a universal second messenger that regulates various aspects of cardiac physiology from contraction rate to the initiation of cardioprotective stress response pathways. Local pools of cAMP are maintained by macromolecular complexes formed by A-kinase anchoring proteins (AKAPs). AKAPs facilitate control by bringing together regulators of the cAMP pathway including G-protein-coupled receptors, ACs, and downstream effectors of cAMP to finely tune signaling. This review will summarize the distinct roles of AC isoforms in cardiac function and how interactions with AKAPs facilitate AC function, highlighting newly appreciated roles for lesser abundant AC isoforms.
Highlights
The heart continuously balances the interplay of various signaling mechanisms in order to maintain homeostasis and respond to stress
Multiple distinct adenylyl cyclase (AC) complexes exist in heart and are important regulators of cardiac physiology
Targeting components of a complex could provide specificity, unlike pan enzyme inhibitors, as these complexes frequently contain only a small percentage of the total protein in the cell. This was the idea behind disrupting the AC5–mAKAP complex as mAKAP-localized cyclic adenosine monophosphate (cAMP) signaling is involved in cardiac hypertrophy [63]
Summary
The heart continuously balances the interplay of various signaling mechanisms in order to maintain homeostasis and respond to stress. HCN channel regulation by cAMP maintains basal heart rate [4] while EPAC facilitates calcium handling and cardiac hypertrophy [5]. Yotiao scaffolds both positive (PKA) and negative regulators, protein phosphatase 1 (PP1) and phosphodiesterase 4DE3 (PDE4D3), of KCNQ1 phosphorylation [80,83,84,85] Loss of this scaffold decreases cAMP-dependent PKA phosphorylation of KCNQ1, eliminates the functional response by IKs, and prolongs the action potential [85]. Yotiao inhibits AC2 and AC3 activity but the mechanism of inhibition is unknown; no inhibition of AC9 activity is observed [87] Based on these results we would postulate that the AC9–Yotiao–PKA–KCNQ1 macromolecular complex generates a local pool of cAMP that is critical for cardiac repolarization in humans
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