5 years ago

BK β1 Subunit-Dependent Facilitation Of Ethanol Inhibition Of BK Current And Cerebral Artery Constriction Is Mediated By The β1 Transmembrane Domain 2

Alex M Dopico, Guruprasad Kuntamallappanavar
Background and Purpose Ethanol at concentrations obtained in circulation during moderate-heavy episodic drinking (30-60 mM) causes cerebral artery constriction in several species, including humans. In rodents, ethanol-induced cerebral artery constriction results from ethanol inhibition of large conductance voltage/Ca2+i-gated potassium (BK) channels in cerebral artery myocytes. Moreover, the smooth muscle-abundant BK β1 accessory subunit is required for ethanol to inhibit cerebral artery myocyte BK channels under physiological Ca2+i and voltages, and thus constrict cerebral arteries. The molecular bases of these ethanol actions remain unknown. Here, we set to identify the BK β1 region(s) that mediates ethanol-induced inhibition of cerebral artery myocyte BK channels and eventual arterial constriction. Experimental Approach We used protein biochemistry, patch-clamp on engineered channel subunits, reversible cDNA permeabilization of KCNMB1 k/o mouse arteries, and artery in vitro pressurization. Key Results Ethanol inhibition of BK current is facilitated by β1 but not β4 subunits. Furthermore, only BK complexes containing β chimeras with β1 TM domains on a β4 background or with a β1 TM2 domain on a β4 background displayed ethanol responses identical to those of BK complexes including wt β1. Moreover, β1 TM2 itself but not other β regions are necessary for ethanol-induced cerebral artery constriction. Conclusion and Implications BK β1 TM2 is necessary for this subunit to enable ethanol-induced inhibition of myocyte BK channels and cerebral artery constriction at physiological Ca2+ and voltages. Thus, novel agents that target β1 TM2 may be considered to counteract ethanol-induced cerebral artery constriction and associated cerebrovascular conditions.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bph.14046

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