Differential distribution and functional impact of BK channel beta1 subunits across mesenteric, coronary, and different cerebral arteries of the rat

Abstract

Large conductance, Ca2+i- and voltage-gated K+ (BK) channels regulate myogenic tone and thus, arterial diameter. In smooth muscle (SM), BK channels include channel-forming α and auxiliary β1 subunits. BK β1 increases the channel’s Ca2+ sensitivity allowing BK channels to negatively feed-back on depolarization-induced Ca2+-entry, oppose SM contraction and favor vasodilation. Thus, endothelial-independent vasodilation can be evoked though targeting of SM BK β1 by endogenous ligands, including lithocholate (LCA). Here, we investigated the expression of BK β1 across arteries of the cerebral and peripheral circulations, and the contribution of such expression to channel function and BK β1–mediated vasodilation. Data demonstrate that endothelium-independent, BK β1-mediated vasodilation by LCA is larger in coronary (CA) and basilar (BA) arteries than in anterior cerebral (ACA), middle cerebral (MCA), posterior cerebral (PCA), and mesenteric (MA) arteries, all arterial segments having a similar diameter. Thus, differential dilation occurs in extracranial arteries which are subjected to similar vascular pressure (CA vs. MA), and in arteries that irrigate different brain regions (BA vs. ACA, MCA, PCA). SM BK channels from BA and CA displayed increased basal activity and LCA responses, indicating increased BK β1 functional presence. Indeed, in the absence of detectable changes in BK α, BA and CA myocytes showed an increased location of BK β1 in the plasmalemma/subplasmalemma. Moreover, these myocytes distinctly showed increased BK β1 mRNA levels. Supporting a major role of enhanced BK β1 transcripts in artery dilation, LCA-induced dilation of MCA transfected with BK β1 cDNA was as high as LCA-induced dilation of untransfected BA or CA.

Molecular structures of the human Slo1 K+ channel in complex with β4

“…The stoichiometry of α and β subunits was assumed generally to be 1:1. Evidence of sub 1:1 stoichiometry emerged from analysis of co-expression in oocytes (Wang et al, 2002) as well as in native tissues (Solaro et al, 1995; Ding et al, 1998; Kuntamallappanavar et al, 2017). It was proposed that a Slo1 channel can contain zero to four β subunits, with each β subunit incrementally influencing channel gating properties (Wang et al, 2002).…”

Regulation of BK Channels by Beta and Gamma Subunits

“…Variable stoichiometry also occurs in native cells, as shown for rat (90) and mouse adrenal CCs (78). Differences in β1:α stoichiometry may also underlie BK channel differences among mesenteric, coronary, and cerebral arteries (91). To what extent variations in average β:α ratios occur for BK currents in other native cells remains largely unexplored.…”

Cholesterol activates BK channels by increasing KCNMB1 protein levels in the plasmalemma

“…To further test the hypothesis that increased KCNMB1 levels in the plasmalemma play a role in CLR-enrichment-driven potentiation of smooth muscle BK current, we evaluated the effect of CLR enrichment in myocytes isolated from basilar (BA) or coronary (CA) artery. These myocytes naturally have higher levels of plasmalemmal KCNMB1 when compared with their MCA counterparts ( 48 ). Consistent with the proposed major role for KCNMB1 levels in CLR potentiation of BK current, CLR enrichment failed to increase BK currents in BA and CA myocytes ( Fig.…”

“…First, as was already proposed for CLR modulation of BK channel’s sensitivity to alcohol, CLR effects on BK channel function might not be monotonic ( 52 ): first, the effect of depleting CLR levels that are naturally present in myocyte membranes may not mirror the effects of enriching native membranes with more CLR. Second, it is important to take into account the exact tissue type and artery type under examination, as even cerebral arteries from the same species exhibit differential levels of plasmalemmal KCNMB1 protein and therefore, differential sensitivity to modulators ( 48 ). In fact, our present data show upregulation of BK channel open probability by CLR enrichment of rat MCA, but not of BA or CA, myocytes ( Fig.…”