Targeting of protein phosphatases PP2A and PP2B to the C-terminus of the L-type calcium channel Cav1.2

Hui Xu, Kenneth S Ginsburg, Duane D. Hall, Maike Zimmermann, Ivar S. Stein, Mingxu Zhang, Samvit Tandan, Joseph A. Hill, Mary C Horne, Donald M Bers, Johannes W Hell

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32 Scopus citations

Abstract

The L-type Ca2+ channel Cav1.2 forms macromolecular signaling complexes that comprise the β2 adrenergic receptor, trimeric Gs protein, adenylyl cyclase, and cAMP-dependent protein kinase (PKA) for efficient signaling in heart and brain. The protein phosphatases PP2A and PP2B are part of this complex. PP2A counteracts increase in Cav1.2 channel activity by PKA and other protein kinases, whereas PP2B can either augment or decrease Cav1.2 currents in cardiomyocytes depending on the precise experimental conditions. We found that PP2A binds to two regions in the C-terminus of the central, pore-forming R1 subunit of Ca v1.2: one region spans residues 1795-1818 and the other residues 1965-1971. PP2B binds immediately downstream of residue 1971. Injection of a peptide that contained residues 1965-1971 and displaced PP2A but not PP2B from endogenous Cav1.2 increased basal and isoproterenol-stimulated L-type Ca 2+ currents in acutely isolated cardiomyocytes. Together with our biochemical data, these physiological results indicate that anchoring of PP2A at this site of Cav1.2 in the heart negatively regulates cardiac L-type currents, likely by counterbalancing basal and stimulated phosphorylation that is mediated by PKA and possibly other kinases.

Original languageEnglish (US)
Pages (from-to)10298-10307
Number of pages10
JournalBiochemistry
Volume49
Issue number48
DOIs
StatePublished - Dec 7 2010

ASJC Scopus subject areas

  • Biochemistry

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    Xu, H., Ginsburg, K. S., Hall, D. D., Zimmermann, M., Stein, I. S., Zhang, M., Tandan, S., Hill, J. A., Horne, M. C., Bers, D. M., & Hell, J. W. (2010). Targeting of protein phosphatases PP2A and PP2B to the C-terminus of the L-type calcium channel Cav1.2. Biochemistry, 49(48), 10298-10307. https://doi.org/10.1021/bi101018c