Progesterone activation of β1-containing BK channels involves two binding sites

Kelsey C. North, Andrew A. Shaw, Anna N. Bukiya and Alex M. Dopico ()
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Kelsey C. North: College of Medicine, The University of Tennessee Health Science Center
Andrew A. Shaw: College of Medicine, The University of Tennessee Health Science Center
Anna N. Bukiya: College of Medicine, The University of Tennessee Health Science Center
Alex M. Dopico: College of Medicine, The University of Tennessee Health Science Center

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Progesterone (≥1 µM) is used in recovery of cerebral ischemia, an effect likely contributed to by cerebrovascular dilation. The targets of this progesterone action are unknown. We report that micromolar (µM) progesterone activates mouse cerebrovascular myocyte BK channels; this action is lost in β1-/- mice myocytes and in lipid bilayers containing BK α subunit homomeric channels but sustained on β1/β4-containing heteromers. Progesterone binds to both regulatory subunits, involving two steroid binding sites conserved in β1-β4: high-affinity (sub-µM), which involves Trp87 in β1 loop, and low-affinity (µM) defined by TM1 Tyr32 and TM2 Trp163. Thus progesterone, but not its oxime, bridges TM1-TM2. Mutation of the high-affinity site blunts channel activation by progesterone underscoring a permissive role of the high-affinity site: progesterone binding to this site enables steroid binding at the low-affinity site, which activates the channel. In support of our model, cerebrovascular dilation evoked by μM progesterone is lost by mutating Tyr32 or Trp163 in β1 whereas these mutations do not affect alcohol-induced cerebrovascular constriction. Furthermore, this alcohol action is effectively counteracted both in vitro and in vivo by progesterone but not by its oxime.

Date: 2023
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DOI: 10.1038/s41467-023-42827-w

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