Ser1928 phosphorylation by PKA stimulates the L-type Ca2+ channel CaV1.2 and vasoconstriction during acute hyperglycemia and diabetes.

Autor: Nystoriak MA; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA., Nieves-Cintrón M; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA., Patriarchi T; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA., Buonarati OR; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA., Prada MP; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA., Morotti S; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA., Grandi E; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA., Fernandes JD; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA., Forbush K; Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, WA 98195, USA., Hofmann F; Department of Pharmacology and Toxicology, Technical University of Munich, Munich D80802, Germany., Sasse KC; Sasse Surgical Associates, Reno, NV 89502, USA., Scott JD; Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, WA 98195, USA., Ward SM; Department of Physiology and Cell Biology, University of Nevada, Reno, NV 89557, USA., Hell JW; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA., Navedo MF; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA. mfnavedo@ucdavis.edu.
Jazyk: angličtina
Zdroj: Science signaling [Sci Signal] 2017 Jan 24; Vol. 10 (463). Date of Electronic Publication: 2017 Jan 24.
DOI: 10.1126/scisignal.aaf9647
Abstrakt: Hypercontractility of arterial myocytes and enhanced vascular tone during diabetes are, in part, attributed to the effects of increased glucose (hyperglycemia) on L-type Ca V 1.2 channels. In murine arterial myocytes, kinase-dependent mechanisms mediate the increase in Ca V 1.2 activity in response to increased extracellular glucose. We identified a subpopulation of the Ca V 1.2 channel pore-forming subunit (α1 C ) within nanometer proximity of protein kinase A (PKA) at the sarcolemma of murine and human arterial myocytes. This arrangement depended upon scaffolding of PKA by an A-kinase anchoring protein 150 (AKAP150) in mice. Glucose-mediated increases in Ca V 1.2 channel activity were associated with PKA activity, leading to α1 C phosphorylation at Ser 1928 Compared to arteries from low-fat diet (LFD)-fed mice and nondiabetic patients, arteries from high-fat diet (HFD)-fed mice and from diabetic patients had increased Ser 1928 phosphorylation and Ca V 1.2 activity. Arterial myocytes and arteries from mice lacking AKAP150 or expressing mutant AKAP150 unable to bind PKA did not exhibit increased Ser 1928 phosphorylation and Ca V 1.2 current density in response to increased glucose or to HFD. Consistent with a functional role for Ser 1928 phosphorylation, arterial myocytes and arteries from knockin mice expressing a Ca V 1.2 with Ser 1928 mutated to alanine (S1928A) lacked glucose-mediated increases in Ca V 1.2 activity and vasoconstriction. Furthermore, the HFD-induced increases in Ca V 1.2 current density and myogenic tone were prevented in S1928A knockin mice. These findings reveal an essential role for α1 C phosphorylation at Ser 1928 in stimulating Ca V 1.2 channel activity and vasoconstriction by AKAP-targeted PKA upon exposure to increased glucose and in diabetes.
(Copyright © 2017, American Association for the Advancement of Science.)
Databáze: MEDLINE
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