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Rationale :Voltage-dependent L-type (CaV 1.2) Ca2+ channels are a heteromeric complex formed from pore-forming α1 and auxiliary α2 δ and β subunits. CaV 1.2 channels are the principal Ca2+ influx pathway in arterial myocytes and regulate multiple physiological functions, including contraction. The macromolecular composition of arterial myocyte CaV 1.2 channels remains poorly understood, with no studies having examined the molecular identity or physiological functions of α2 δ subunits.Objective :We investigated the functional significance of α2 δ subunits in myocytes of resistance-size (100 to 200 μm diameter) cerebral arteries.Methods and Results :α2 δ-1 was the only α2 δ isoform expressed in cerebral artery myocytes. Pregabalin, an α2 δ-1/-2 ligand, and an α2 δ-1 antibody, inhibited CaV 1.2 currents in isolated myocytes. Acute pregabalin application reversibly dilated pressurized arteries. Using a novel application of surface biotinylation, data indicated that &gt;95% of CaV 1.2 α1 and α2 δ-1 subunits were present in the arterial myocyte plasma membrane. α2 δ-1 knockdown using short hairpin RNA reduced plasma membrane-localized CaV 1.2 α1 subunits, caused a corresponding elevation in cytosolic CaV 1.2 α1 subunits, decreased intracellular Ca2+ concentration, inhibited pressure-induced vasoconstriction (“myogenic tone”), and attenuated pregabalin-induced vasodilation. Prolonged (24-hour) pregabalin exposure did not alter total α2 δ-1 or CaV 1.2 α1 proteins but decreased plasma membrane expression of each subunit, which reduced myogenic tone.Conclusions :α2 δ-1 is essential for plasma membrane expression of arterial myocyte CaV 1.2 α1 subunits. α2 δ-1 targeting can block CaV 1.2 channels directly and inhibit surface expression of CaV 1.2 α1 subunits, leading to vasodilation. These data identify α2 δ-1 as a novel molecular target in arterial myocytes, the manipulation of which regulates contractility.

Smooth Muscle Cell α 2 δ-1 Subunits Are Essential for Vasoregulation by Ca V 1.2 Channels

Smooth Muscle Cell α ₂ δ-1 Subunits Are Essential for Vasoregulation by Ca _V 1.2 Channels