Critical role of cAMP-dependent protein kinase anchoring to the L-type calcium channel Cav1.2 via A-kinase anchor protein 150 in neurons

Duane D. Hall, Monika A. Davare, Mei Shi, Margaret L. Allen, Michael Weisenhaus, G. Stanley McKnight, Johannes W. Hell

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

The cAMP-dependent protein kinase (PKA) regulates a wide array of cellular functions. In brain and heart PKA increases the activity of the L-type Ca 2+ channel Cav1.2 in response to β-adrenergic stimulation. Cav1.2 forms a complex with the β2- adrenergic receptor, the trimeric GS protein, adenylyl cyclase, and PKA wherein highly localized signaling occurs [Davare, M. A., Avdonin, V., Hall, D. D., Peden, E. M., Burette, A., Weinberg, R. J., Horne, M. C., Hoshi, T., and Hell, J. W. (2001) Science 293, 98-101]. PKA primarily phosphorylates Ca v1.2 on serine 1928 of the central, pore-forming α 11.2 subunit. Here we demonstrate that the A-kinase anchor protein 150 (AKAP150) is critical for PKA-mediated regulation of Cav1.2 in the brain. AKAP150 and MAP2B specifically co-immunoprecipitate with Ca v1.2 from rat brain. Recombinant AKAP75, the bovine homologue to rat AKAP150, binds directly to three different sites of α11.2. MAP2B from rat brain also interacts with these same sites in pull-down assays. Gene disruption of AKAP150 in mice dramatically reduces co-immunoprecipitation of PKA with Cav1.2 and prevents phosphorylation of serine 1928 upon β-adrenergic stimulation in vivo. These results demonstrate the physiological relevance of PKA anchoring by AKAPs in general and AKAP150 specifically in the regulation of Cav1.2 in vivo.

Original languageEnglish (US)
Pages (from-to)1635-1646
Number of pages12
JournalBiochemistry
Volume46
Issue number6
DOIs
StatePublished - Feb 13 2007

ASJC Scopus subject areas

  • Biochemistry

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