Martín-Aragón Baudel M, Flores-Tamez V A, Hong J, et al. Spatiotemporal control of vascular CaV1. 2 by α1c S1928 phosphorylation[J]. Circulation Research, 2022, 131(12): 1018-1033.
Journal: Circulation Research
Background and Customer Requirements:
1) L-type CaV1.2 channels undergo cooperative gating to regulate cell function, although mechanisms are unclear.
2) This study aim to test the hypothesis that phosphorylation of the CaV1.2 pore-forming subunit α-1C at S1928 mediates vascular CaV1.2 cooperativity during diabetic hyperglycemia.
Demands of the Research:
The main purpose of this study was to investigate the effect of phosphorylation of the CaV1.2 pore-forming subunit α-1C at S1928 mediates vascular CaV1.2 cooperativity. And it is crucial to get the blood flow to assess the effect.
Clear to see that representative pseudo-colored blood flow images of WT and S1928A cerebral pial arteries through a cranial window exposed to 10 mmol/L D-glu, 20 mmol/L D-glu or 0 Ca2+ vasodilatory mix, which confirms that pS1928 is necessary for increased arterial myocyte Ca2+ and contractility upon HG.
Results and Effects:
1) CaV1.2 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，which was prevented in wild-type cells pre-exposed to a PKA inhibitor or cells from knock-in S1928A but not S1700A mice.
2) α-1C 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.
3) 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.
4) The results may lay the foundation for developing therapeutics to correct CaV1.2 and arterial function during diabetic hyperglycemia.
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