Hypercontractility of arterial myocytes and enhanced vascular tone during diabetes are, in part, attributed to the effects of increased glucose (hyperglycemia) on L-type Ca1.2 channels. In murine arterial myocytes, kinase-dependent mechanisms mediate the increase in Ca1.2 activity in response to increased extracellular glucose. We identified a subpopulation of the Ca1.2 channel pore-forming subunit (?1) within nanometer proximity of protein kinase A (PKA) at the sarcolemma of murine and human arterial myocytes. This arrangement depended upon scaffolding of PKA by an A-kinase anchoring protein 150 (AKAP150) in mice. Glucose-mediated increases in Ca1.2 channel activity were associated with PKA activity, leading to ?1 phosphorylation at Ser Compared to arteries from low-fat diet (LFD)-fed mice and nondiabetic patients, arteries from high-fat diet (HFD)-fed mice and from diabetic patients had increased Ser phosphorylation and Ca1.2 activity. Arterial myocytes and arteries from mice lacking AKAP150 or expressing mutant AKAP150 unable to bind PKA did not exhibit increased Ser phosphorylation and Ca1.2 current density in response to increased glucose or to HFD. Consistent with a functional role for Ser phosphorylation, arterial myocytes and arteries from knockin mice expressing a Ca1.2 with Ser mutated to alanine (S1928A) lacked glucose-mediated increases in Ca1.2 activity and vasoconstriction. Furthermore, the HFD-induced increases in Ca1.2 current density and myogenic tone were prevented in S1928A knockin mice. These findings reveal an essential role for ?1 phosphorylation at Ser in stimulating Ca1.2 channel activity and vasoconstriction by AKAP-targeted PKA upon exposure to increased glucose and in diabetes.     «

Hypercontractility of arterial myocytes and enhanced vascular tone during diabetes are, in part, attributed to the effects of increased glucose (hyperglycemia) on L-type Ca1.2 channels. In murine arterial myocytes, kinase-dependent mechanisms mediate the increase in Ca1.2 activity in response to increased extracellular glucose. We identified a subpopulation of the Ca1.2 channel pore-forming subunit (?1) within nanometer proximity of protein kinase A (PKA) at the sarcolemma of murine and human ar...     »