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

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Sci. Signal.  24 Jan 2017:
Vol. 10, Issue 463, eaaf9647
DOI: 10.1126/scisignal.aaf9647

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How sugar constricts arteries

Pathological vasoconstriction compromises blood flow to tissues and contributes to various conditions associated with diabetes, including stroke, hypertension, diabetic neuropathy, and diabetic retinopathy. Nystoriak et al. identified a molecular signaling complex—protein kinase A, a scaffolding protein in the AKAP family, and the L-type calcium channel CaV1.2—in arterial myocytes from mice that mediates the phosphorylation of CaV1.2 and enhances the activity of this channel, leading to vasoconstriction. Exposing isolated arterial myocytes from mice or humans to increased extracellular glucose promoted this modification and increased channel activity. Furthermore, myocytes from diabetic mice or human diabetic subjects had increased amount of phosphorylation of CaV1.2 at Ser1928, which resulted in increased channel activity. Arteries from the diabetic mice exhibited a more pronounced vasoconstriction response to pressure than did arteries from control mice. Knocking in S1928A mutant form of the channel blocked this response. Thus, targeting this CaV1.2 regulatory complex may prevent vascular dysfunction in diabetic patients.