Mice With Disrupted BK Channel β1 Subunit Gene Feature Abnormal Ca ²⁺ Spark/STOC Coupling and Elevated Blood Pressure

Abstract

Large-conductance potassium (BK) channels in vascular smooth muscle cells (VSMCs) sense both changes in membrane potential and in intracellular Ca(2+) concentration. BK channels may serve as negative feedback regulators of vascular tone by linking membrane depolarization and local increases in intracellular Ca(2+) concentration (Ca(2+) sparks) to repolarizing spontaneous transient outward K(+) currents (STOCs). BK channels are composed of channel-forming BKalpha and auxiliary BKbeta1 subunits, which confer to BK channels an increased sensitivity for changes in membrane potential and Ca(2+). To assess the in vivo functions of this ss subunit, mice with a disrupted BKbeta1 gene were generated. Cerebral artery VSMCs from BKbeta1 -/- mice generated Ca(2+) sparks of normal amplitude and frequency, but STOC frequencies were largely reduced at physiological membrane potentials. Our results indicate that BKbeta1 -/- mice have an abnormal Ca(2+) spark/STOC coupling that is shifted to more depolarized potentials. Thoracic aortic rings from BKbeta1 -/- mice responded to agonist and elevated KCl with a increased contractility. BKbeta1 -/- mice had higher systemic blood pressure than BKbeta1 +/+ mice but responded normally to alpha(1)-adrenergic vasoconstriction and nitric oxide-mediated vasodilation. We propose that the elevated blood pressure in BKbeta1 -/- mice serves to normalize Ca(2+) spark/STOC coupling for regulating myogenic tone. The full text of this article is available at http://www.circresaha.org.

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca 2+ -activated K + channel deficiency

“…The consequences of BK channel ablation exceed by far those caused by deletion of the regulatory BK channel ␤ 1 subunit, which is not significantly expressed in neurons and produced no neural effects (33,34). Nevertheless, the BK channels, despite their widespread expression in the CNS (24), appear to play surprisingly modest roles in normal brain function.…”

Activation of NFATc3 Down-regulates the β1 Subunit of Large Conductance, Calcium-activated K+ Channels in Arterial Smooth Muscle and Contributes to Hypertension

“…Taken together, these data suggest that whereas angiotensin II-mediated increases in Ca 2ϩ entry through L-type Ca 2ϩ channels are necessary for NFAT activation and ␤1 subunit down-regulation, an increase in [Ca 2ϩ ] i by itself is not a sufficient stimulus to decrease expression of this BK channel subunit. (3,7). Thus, it is reasonable to hypothesize that angiotensin II infusion into NFATc3 Ϫ/Ϫ mice would either not increase blood pressure or increase it to a lesser extent than in WT mice (Fig.…”

“…The functional relevance of the ␤1 subunit of the BK channel was underscored in a recent series of studies, which demonstrated that in ␤1 null mice, arterial smooth muscle BK channels had lower Ca 2ϩ sensitivities than their wild type counterparts. Consequently, these BK channels were decoupled from Ca 2ϩ sparks, which resulted in depolarized arterial smooth muscle, increased vasoconstriction, and ultimately hypertension (3,7).…”

KCNMB1 genotype influences response to verapamil SR and adverse outcomes in the INternational VErapamil SR/Trandolapril STudy (INVEST)

“…The gene that encodes the β1 subunit of the BK channel is KCNMB1, located on chromosome 5q34. KCNMB1 knockout mice have decreased calcium sensitivity, elevated blood pressure (BP), and cardiac hypertrophy [2,3].…”