Evidence for modulation of Shaker ‐type (K v 1) channels in rat small cerebral arteries by ancillary K v β 2 subunits

Abstract

Voltage-gated K+ (Kv) channels in vascular smooth muscle cells (VSMCs) mediate vasodilation, and their loss is linked to abnormal vascular reactivity. We recently demonstrated that Kv channels in rat small cerebral arteries represent pore-forming Kv1.2/1.5α tetramers, which associate with ancillary Kvβ2 subunits. Based on a chaperoning role for Kvβ2 in nonvascular tissues, we hypothesized that Kvβ2 is required for the normal expression of Kv channels in cerebral VSMCs. Cultured rat cerebral VSMCs were electroporated with 10μg of Kvβ2-specific siRNA for 48 hours. Kvβ2 was knocked down in VSMCs treated with siRNA compared to scrambled sequence. This event was associated with a concomitant decrease in the mature glycosylated Kv1.2α subunits that compose the Kv channel tetramers; an increase in immature Kv1.2α was detected. In further studies, we evaluated if the reduced expression of Kv channels in abnormally reactive cerebral arteries from hypertensive rats is associated with a loss of Kvβ2 subunits. Indeed, cerebral arteries from two different rat models of hypertension showed abnormally low levels of Kvβ2. Collectively, these results suggest that Kvβ2 subunits promote anterograde trafficking and expression of Kv channels in cerebral VSMCs, and that a loss of Kvβ2 is associated with reduced Kv channel expression and cerebral vasoconstriction during hypertensive disease. (Supported by HL-59238-08).