Spatiotemporal Control of Vascular Ca V 1.2 by α1 C S1928 Phosphorylation.

Autor: Martín-Aragón Baudel M; Department of Pharmacology, University of California Davis, Davis, CA (M.M.-A.B., V.A.F.-T., J.H., G.R.R., A.E.B., K.N.M.M., D.M.B., J.W.H., M.N.-C., M.F.N.)., Flores-Tamez VA; Department of Pharmacology, University of California Davis, Davis, CA (M.M.-A.B., V.A.F.-T., J.H., G.R.R., A.E.B., K.N.M.M., D.M.B., J.W.H., M.N.-C., M.F.N.)., Hong J; Department of Pharmacology, University of California Davis, Davis, CA (M.M.-A.B., V.A.F.-T., J.H., G.R.R., A.E.B., K.N.M.M., D.M.B., J.W.H., M.N.-C., M.F.N.)., Reddy GR; Department of Pharmacology, University of California Davis, Davis, CA (M.M.-A.B., V.A.F.-T., J.H., G.R.R., A.E.B., K.N.M.M., D.M.B., J.W.H., M.N.-C., M.F.N.)., Maillard P; Department of Neurology, University of California Davis, Davis, CA (P.M.)., Burns AE; Department of Pharmacology, University of California Davis, Davis, CA (M.M.-A.B., V.A.F.-T., J.H., G.R.R., A.E.B., K.N.M.M., D.M.B., J.W.H., M.N.-C., M.F.N.)., Man KNM; Department of Pharmacology, University of California Davis, Davis, CA (M.M.-A.B., V.A.F.-T., J.H., G.R.R., A.E.B., K.N.M.M., D.M.B., J.W.H., M.N.-C., M.F.N.)., Sasse KC; Sasse Surgical Associates, Reno, NV (K.C.S.)., Ward SM; Department of Physiology and Cell Biology, University of Nevada Reno, Reno, NV (S.M.W.)., Catterall WA; Department of Pharmacology, University of Washington, Seattle, WA (W.A.C.)., Bers DM; Department of Pharmacology, University of California Davis, Davis, CA (M.M.-A.B., V.A.F.-T., J.H., G.R.R., A.E.B., K.N.M.M., D.M.B., J.W.H., M.N.-C., M.F.N.)., Hell JW; Department of Pharmacology, University of California Davis, Davis, CA (M.M.-A.B., V.A.F.-T., J.H., G.R.R., A.E.B., K.N.M.M., D.M.B., J.W.H., M.N.-C., M.F.N.)., Nieves-Cintrón M; Department of Pharmacology, University of California Davis, Davis, CA (M.M.-A.B., V.A.F.-T., J.H., G.R.R., A.E.B., K.N.M.M., D.M.B., J.W.H., M.N.-C., M.F.N.)., Navedo MF; Department of Pharmacology, University of California Davis, Davis, CA (M.M.-A.B., V.A.F.-T., J.H., G.R.R., A.E.B., K.N.M.M., D.M.B., J.W.H., M.N.-C., M.F.N.).
Jazyk: angličtina
Zdroj: Circulation research [Circ Res] 2022 Dec 02; Vol. 131 (12), pp. 1018-1033. Date of Electronic Publication: 2022 Nov 08.
DOI: 10.1161/CIRCRESAHA.122.321479
Abstrakt: Background: L-type Ca V 1.2 channels undergo cooperative gating to regulate cell function, although mechanisms are unclear. This study tests the hypothesis that phosphorylation of the Ca V 1.2 pore-forming subunit α1 C at S1928 mediates vascular Ca V 1.2 cooperativity during diabetic hyperglycemia.
Methods: A multiscale approach including patch-clamp electrophysiology, super-resolution nanoscopy, proximity ligation assay, calcium imaging' pressure myography, and Laser Speckle imaging was implemented to examine Ca V 1.2 cooperativity, α1 C clustering, myogenic tone, and blood flow in human and mouse arterial myocytes/vessels.
Results: Ca V 1.2 activity and cooperative gating increase in arterial myocytes from patients with type 2 diabetes and type 1 diabetic mice, and in wild-type mouse arterial myocytes after elevating extracellular glucose. These changes were prevented in wild-type cells pre-exposed to a PKA inhibitor or cells from knock-in S1928A but not S1700A mice. In addition, α1 C clustering at the surface membrane of wild-type, but not wild-type cells pre-exposed to PKA or P2Y 11 inhibitors and S1928A arterial myocytes, was elevated upon hyperglycemia and diabetes. Ca V 1.2 spatial and gating remodeling correlated with enhanced arterial myocyte Ca 2+ influx and contractility and in vivo reduction in arterial diameter and blood flow upon hyperglycemia and diabetes in wild-type but not S1928A cells/mice.
Conclusions: These results suggest that PKA-dependent S1928 phosphorylation promotes the spatial reorganization of vascular α1 C into "superclusters" upon hyperglycemia and diabetes. This triggers Ca V 1.2 activity and cooperativity, directly impacting vascular reactivity. The results may lay the foundation for developing therapeutics to correct Ca V 1.2 and arterial function during diabetic hyperglycemia.
Databáze: MEDLINE
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