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Mechanisms underlying regional differences in the Ca2+ sensitivity of BKCa current in arteriolar smooth muscle.

Yan Yang, Yoshiro Sohma, Zahra Nourian, Srikanth R Ella, Min Li, Aaron Stupica, Ronald J Korthuis, Michael J Davis, Andrew P Braun, Michael A Hill

J. Physiol. (Lond.), 2013 Mar 1 , 591, 1277-93

Abstract  β1-Subunits enhance the gating properties of large-conductance Ca-activated K channels (BK) formed by α-subunits. In arterial vascular smooth muscle cells (VSMCs), β1-subunits are vital in coupling SR-generated Ca sparks to BK activation, affecting contractility and blood pressure. Studies in cremaster and cerebral VSMCs show heterogeneity of BK activity due to apparent differences in the functional β1-subunit:α-subunit ratio. To define these differences, studies were conducted at the single-channel level while siRNA was used to manipulate specific subunit expression. β1 modulation of the α-subunit Ca sensitivity was studied using patch-clamp techniques. BK channel normalized open probability (NP) versus membrane potential (V) curves were more left-shifted in cerebral versus cremaster VSMCs as cytoplasmic Ca was raised from 0.5 to 100 μm. Calculated V values of channel activation decreased from 72.0 ± 6.1 at 0.5 μm Ca to -89 ± 9 mV at 100 μm Ca in cerebral compared with 101 ± 10 to -63 ± 7 mV in cremaster VSMCs. Cremaster BK channels thus demonstrated an ∼2.5-fold weaker apparent Ca sensitivity such that at a value of V of -30 mV, a mean value of [Ca] of 39 μm was required to open half of the channels in cremaster versus 16 μm [Ca] in cerebral VSMCs. Further, shortened mean open and longer mean closed times were evident in BK channel events from cremaster VSMCs at either -30 or 30 mV at any given [Ca]. β1-Subunit-directed siRNA decreased both the apparent Ca sensitivity of BK in cerebral VSMCs and the appearance of spontaneous transient outward currents. The data are consistent with a higher ratio of β-subunit:α-subunit of BK channels in cerebral compared with cremaster VSMCs. Functionally, this leads both to higher Ca sensitivity and NP for BK channels in the cerebral vasculature relative to that of skeletal muscle.