RGD Reference Report - Beta-adrenergic regulation requires direct anchoring of PKA to cardiac CaV1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15.

General

Beta-adrenergic regulation requires direct anchoring of PKA to cardiac CaV1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15.
Authors:	Hulme, JT Lin, TW Westenbroek, RE Scheuer, T Catterall, WA
Citation:	Hulme JT, etal., Proc Natl Acad Sci U S A 2003 Oct 28;100(22):13093-8. Epub 2003 Oct 20.
RGD ID:	1304018
Pubmed:	PMID:14569017 (View Abstract at PubMed)
PMCID:	PMC240750 (View Article at PubMed Central)
DOI:	DOI:10.1073/pnas.2135335100 (Journal Full-text)
Activation of beta-adrenergic receptors and consequent phosphorylation by cAMP-dependent protein kinase A (PKA) greatly increases the L-type Ca2+ current through CaV1.2 channels in isolated cardiac myocytes. A kinase-anchoring protein 15 (AKAP15) coimmunoprecipitates with CaV1.2 channels isolated from rat heart membrane extracts and transfected cells, and it colocalizes with CaV1.2 channels and PKA in the transverse tubules of isolated ventricular myocytes. Site-directed mutagenesis studies reveal that AKAP15 directly interacts with the distal C terminus of the cardiac CaV1.2 channel via a leucine zipper-like motif. Disruption of PKA anchoring to CaV1.2 channels via AKAP15 using competing peptides markedly inhibits the beta-adrenergic regulation of CaV1.2 channels via the PKA pathway in ventricular myocytes. These results identify a conserved leucine zipper motif in the C terminus of the CaV1 family of Ca2+ channels that directly anchors an AKAP15-PKA signaling complex to ensure rapid and efficient regulation of L-type Ca2+ currents in response to beta-adrenergic stimulation and local increases in cAMP.

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Cellular Component

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
T-tubule		IDA		1304018; 1304018; 1304018		RGD

Molecular Function

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
protein binding		IPI	Cacna1c (Rattus norvegicus)	1304018	protein C-terminus binding	RGD
protein domain specific binding		IPI	Akap7 (Rattus norvegicus)	1304018		RGD
protein kinase A binding		TAS		1304018		RGD

Objects Annotated

Genes (Rattus norvegicus)

Akap7 (A-kinase anchoring protein 7)

Cacna1c (calcium voltage-gated channel subunit alpha1 C)

Prkar2a (protein kinase cAMP-dependent type II regulatory subunit alpha)

Additional Information

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Beta-adrenergic regulation requires direct anchoring of PKA to cardiac CaV1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15.