Targeting of protein phosphatases PP2A and PP2B to the C-terminus of the L-type calcium channel Ca v1.2.
The L-type Ca(2+) channel Ca(v)1.2 forms macromolecular signaling complexes that comprise the β(2) adrenergic receptor, trimeric G(s) 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 Ca(v)1.2 channel activity by PKA and other protein kinases, whereas PP2B can either augment or decrease Ca(v)1.2 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 α(1) subunit of Ca(v)1.2: 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 Ca(v)1.2 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 Ca(v)1.2 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.
Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1109, USA.
Hui
H
Xu
Kenneth S
KS
Ginsburg
Duane D
DD
Hall
Maike
M
Zimmermann
Ivar S
IS
Stein
Mingxu
M
Zhang
Samvit
S
Tandan
Joseph A
JA
Hill
Mary C
MC
Horne
Donald
D
Bers
Johannes W
JW
Hell
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D019703:Calcineurin / Q000737:chemistry / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000378:metabolism*; D004553:Electric Conductivity; D051379:Mice; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010477:Perfusion; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000378:metabolism*; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism
D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D010446:Peptide Fragments; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D019703:Calcineurin; D054648:Protein Phosphatase 2