Adenylyl cyclase--A-kinase anchoring protein complexes: the next dimension in cAMP signaling

Abstract

The formation of multiprotein complexes is a repeated theme in biology ranging from the regulation of the extracellular signal-regulated kinase and cAMP signaling pathways to the formation of postsynaptic density complexes or tight junctions. A-kinase anchoring proteins (AKAPs) are well known for their ability to scaffold protein kinase A and components upstream and downstream of cAMP production, including G protein-coupled receptors, cAMP-dependent Rap-exchange factors, and phosphodiesterases. Specific adenylyl cyclase (AC) isoforms have also been identified as components of AKAP complexes, namely AKAP79, Yotiao, and mAKAP. In this review, we summarize recent evidence for AC-AKAP complexes and requirements for compartmentalization of cAMP signaling. The ability of AKAPs to assemble intricate feedback loops to control spatiotemporal aspects of cAMP signaling adds yet another dimension to the classic cAMP pathway.

Fig. 1.

Regulation of AC isoforms. General patterns of regulation are shown for individual isoforms and, where appropriate, closely related ACs. Broken lines indicate modes of regulation that differ between grouped isoforms. AKAPs known to associate with AC isoforms are indicated. For simplicity, not all forms of regulation are shown. CAM, calmodulin; CNG, cyclic nucleotide-gated channel; G_s, heterotrimeric Gα_s · βγ; PAM, protein activator of myc; PI3K, phosphatidylinositol-3-kinase; RGS, regulator of G protein signaling.

Fig. 2.

AC-AKAP assembled complexes. A, AKAP79 coordinates different protein combinations to tailor effector regulation in different tissues. Anchored PKA can phosphorylate and inhibit bound AC5/6 and desensitize anchored βAR, in addition to regulation of associated downstream effectors. B, Yotiao binds to AC2, in addition to AC 1, 3, and 9. The anchoring of a PKA-regulated PDE sets up potential feedback regulation of cAMP levels independent of Yotiao-mediated inhibition of AC2. C, mAKAPβ complexes assembled on the nuclear envelope. In this model, βAR-stimulated AC5 increases cAMP to activate anchored PKA and potentially EPAC. PKA phosphorylation of the ryanodine receptor (RyR) increases channel activity to allow for Ca²⁺ activation of CaN. Several feedback loops are also initiated, including PKA-dependent inhibition of AC5 to decrease cAMP synthesis and activation of PDE4D3 by PKA to increase cAMP breakdown. The binding of ERK1/2 to PDE4D3 is not shown. [Adapted from Kapiloff MS, Piggott LA, Sadana R, Li J, Heredia LA, Henson E, Efendiev R, and Dessauer CW (2009) An adenylyl cyclase-mAKAPβ signaling complex regulates cAMP levels in cardiac myocytes. J Biol Chem 284:23540–23546. Copyright © 2009 American Society for Biochemistry and Molecular Biology. Used with permission.]