title: CaV1.2 signaling complexes in the heart.
abstract: L-type Ca(2+) channels (LTCCs) are essential for generation of the electrical and mechanical properties of cardiac muscle. Furthermore, regulation of LTCC activity plays a central role in mediating the effects of sympathetic stimulation on the heart. The primary mechanism responsible for this regulation involves β-adrenergic receptor (βAR) stimulation of cAMP production and subsequent activation of protein kinase A (PKA). Although it is well established that PKA-dependent phosphorylation regulates LTCC function, there is still much we do not understand. However, it has recently become clear that the interaction of the various signaling proteins involved is not left to completely stochastic events due to random diffusion. The primary LTCC expressed in cardiac muscle, CaV1.2, forms a supramolecular signaling complex that includes the β2AR, G proteins, adenylyl cyclases, phosphodiesterases, PKA, and protein phosphatases. In some cases, the protein interactions with CaV1.2 appear to be direct, in other cases they involve scaffolding proteins such as A kinase anchoring proteins and caveolin-3. Functional evidence also suggests that the targeting of these signaling proteins to specific membrane domains plays a critical role in maintaining the fidelity of receptor mediated LTCC regulation. This information helps explain the phenomenon of compartmentation, whereby different receptors, all linked to the production of a common diffusible second messenger, can vary in their ability to regulate LTCC activity. The purpose of this review is to examine our current understanding of the signaling complexes involved in cardiac LTCC regulation.
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA. rdharvey@unr.edu
authors.forename: Robert D
authors.initials: RD
authors.lastname: Harvey
authors.forename: Johannes W
authors.initials: JW
authors.lastname: Hell
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism* / Q000502:physiology; D020013:Calcium Signaling; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D011943:Receptors, Adrenergic, beta; D018078:Receptors, Prostaglandin E; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium