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Spatiotemporal Control of Vascular CaV1.2 by α1C S1928 Phosphorylation

Circulation research, 2022-12, Vol.131 (12), p.1018-1033 [Peer Reviewed Journal]

2022 The Authors. 2022 ;ISSN: 0009-7330 ;EISSN: 1524-4571 ;DOI: 10.1161/CIRCRESAHA.122.321479 ;PMID: 36345826

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  • Title:
    Spatiotemporal Control of Vascular CaV1.2 by α1C S1928 Phosphorylation
  • Author: Martín-Aragón Baudel, Miguel ; Flores-Tamez, Victor A ; Hong, Junyoung ; Reddy, Gopyreddy R ; Maillard, Pauline ; Burns, Abby E ; Man, Kwun Nok Mimi ; Sasse, Kent C ; Ward, Sean M ; Catterall, William A ; Bers, Donald M ; Hell, Johannes W ; Nieves-Cintrón, Madeline ; Navedo, Manuel F
  • Subjects: Original Research
  • Is Part Of: Circulation research, 2022-12, Vol.131 (12), p.1018-1033
  • Description: BACKGROUNDL-type CaV1.2 channels undergo cooperative gating to regulate cell function, although mechanisms are unclear. This study tests the hypothesis that phosphorylation of the CaV1.2 pore-forming subunit α1C at S1928 mediates vascular CaV1.2 cooperativity during diabetic hyperglycemia.METHODSA multiscale approach including patch-clamp electrophysiology, super-resolution nanoscopy, proximity ligation assay, calcium imaging' pressure myography, and Laser Speckle imaging was implemented to examine CaV1.2 cooperativity, α1C clustering, myogenic tone, and blood flow in human and mouse arterial myocytes/vessels.RESULTSCaV1.2 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, α1C clustering at the surface membrane of wild-type, but not wild-type cells pre-exposed to PKA or P2Y11 inhibitors and S1928A arterial myocytes, was elevated upon hyperglycemia and diabetes. CaV1.2 spatial and gating remodeling correlated with enhanced arterial myocyte Ca2+ 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.CONCLUSIONSThese results suggest that PKA-dependent S1928 phosphorylation promotes the spatial reorganization of vascular α1C into "superclusters" upon hyperglycemia and diabetes. This triggers CaV1.2 activity and cooperativity, directly impacting vascular reactivity. The results may lay the foundation for developing therapeutics to correct CaV1.2 and arterial function during diabetic hyperglycemia.
  • Publisher: Hagerstown, MD: Lippincott Williams & Wilkins
  • Language: English
  • Identifier: ISSN: 0009-7330
    EISSN: 1524-4571
    DOI: 10.1161/CIRCRESAHA.122.321479
    PMID: 36345826
  • Source: GFMER Free Medical Journals
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