The Slo1 Y450F Substitution Modifies Basal Function and Cholesterol Response of Middle Cerebral Artery Smooth Muscle BK Channels in a Sexually Dimorphic Manner

TL;DR

A genetic change in BK channels affects their function and response to cholesterol in male mice's brain arteries, but not their artery size.

Contribution

The study reveals a sex-specific effect of the Y450F substitution on BK channel function and cholesterol response in cerebral artery smooth muscle.

Findings

The Y450F substitution alters BK channel function and cholesterol response in male smooth muscle cells.

The mutation does not affect middle cerebral artery diameter ex vivo.

Sexual dimorphism is observed in the effects of the Y450F substitution on BK channels.

Abstract

Calcium- and voltage-gated potassium channels of large conductance (BK channels) in smooth muscle (SM) act as part of a negative feedback mechanism on SM contraction and associated decrease in cerebral artery diameter. Functional BK channels result from tetrameric association of α subunits encoded by KCNMA1 (Slo1). Ionic current from slo1 channels is inhibited by cholesterol in artificial lipid bilayers, an effect significantly reduced by the slo1 Y450F substitution. Whether such substitution affects cholesterol action on cerebral artery SM BK channel function and diameter remains unknown. Using the KCNMA1Y450F knock-in (K/I) mouse, we determined the effect of cholesterol enrichment on BK currents in native SM cells from middle cerebral artery using patch-clamp electrophysiology and the artery diameter ex vivo response to cholesterol. Results show that the KCNMA1Y450F K/I mutation modifies both basal function and the channel’s response to cholesterol enrichment. Such modifications are detectable solely in SM cells from males, demonstrating sexual dimorphism. Unexpectedly, the modifications introduced by the Y450F substitution do not translate into observable changes in middle cerebral artery diameter ex vivo, suggesting that mechanisms at the SM level compensate for changes driven by the KCNMA1 point mutation under study.

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