Predominant contribution of L-type Cav1.2 channel stimulation to impaired intracellular calcium and cerebral artery vasoconstriction in diabetic hyperglycemia.

Enhanced L-type Ca2+ channel (LTCC) activity in arterial myocytes contributes to vascular dysfunction during diabetes. Modulation of LTCC activity under hyperglycemic conditions could result from membrane potential-dependent and independent mechanisms. We have demonstrated that elevations in extracellular glucose (HG), similar to hyperglycemic conditions during diabetes, stimulate LTCC activity through phosphorylation of CaV 1.2 at serine 1928. Prior studies have also shown that HG can suppress the activity of K+ channels in arterial myocytes, which may contribute to vasoconstriction via membrane depolarization. Here, we used a mathematical model of membrane and Ca2+ dynamics in arterial myocytes to predict the relative roles of LTCC and K+ channel activity in modulating global Ca2+ in response to HG. Our data revealed that abolishing LTCC potentiation normalizes [Ca2+ ]i , despite the concomitant reduction in K+ currents in response to HG. These results suggest that LTCC stimulation may be the primary mechanism underlying vasoconstriction during hyperglycemia.