α1C S1928 Phosphorylation of CaV1.2 Channel Controls Vascular Reactivity and Blood Pressure

Abstract

Background Increased vascular CaV1.2 channel function causes enhanced arterial tone during hypertension. This is mediated by elevations in angiotensin II/protein kinase C signaling. Yet, the mechanisms underlying these changes are unclear. We hypothesize that α1C phosphorylation at serine 1928 (S1928) is a key event mediating increased CaV1.2 channel function and vascular reactivity during angiotensin II signaling and hypertension. Methods and Results The hypothesis was examined in freshly isolated mesenteric arteries and arterial myocytes from control and angiotensin II‐infused mice. Specific techniques include superresolution imaging, proximity ligation assay, patch‐clamp electrophysiology, Ca2+ imaging, pressure myography, laser speckle imaging, and blood pressure telemetry. Hierarchical “nested” and appropriate parametric or nonparametric t test and ANOVAs were used to assess statistical differences. We found that angiotensin II redistributed the CaV1.2 pore‐forming α1C subunit into larger clusters. This was correlated with elevated CaV1.2 channel activity and cooperativity, global intracellular Ca2+ and contraction of arterial myocytes, enhanced myogenic tone, and altered blood flow in wild‐type mice. These angiotensin II‐induced changes were prevented/ameliorated in cells/arteries from S1928 mutated to alanine knockin mice, which contain a negative modulation of the α1C S1928 phosphorylation site. In angiotensin II‐induced hypertension, increased α1C clustering, CaV1.2 activity and cooperativity, myogenic tone, and blood pressure in wild‐type cells/tissue/mice were averted/reduced in S1928 mutated to alanine samples. Conclusions Results suggest an essential role for α1C S1928 phosphorylation in regulating channel distribution, activity and gating modality, and vascular function during angiotensin II signaling and hypertension. Phosphorylation of this single vascular α1C amino acid could be a risk factor for hypertension that may be targeted for therapeutic intervention.

Keywords

• cardiovascular
• clustering
• cooperativity
• diabetes
• hypertension