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Ball-and-chain inactivation of a human large conductance calcium-activated potassium channel

S. Agarwal,Elizabeth D. Kim,Sangyun Lee,A. Simon,Alessio Accardi,C. Nimigean

Published 2025 in Nature Communications

ABSTRACT

BK channels are large-conductance calcium (Ca2+)-activated potassium channels crucial for neuronal excitability, muscle contraction, and neurotransmitter release. The pore-forming (α) subunits co-assemble with auxiliary (β and γ) subunits that modulate their function. Previous studies demonstrated that the N-termini of β2-subunits can inactivate BK channels, but with no structural correlate. Here, we investigate BK β2-subunit inactivation using cryo-electron microscopy, electrophysiology and molecular dynamics simulations. We find that the β2 N-terminus occludes the pore only in the Ca2+-bound open state, via a ball-and-chain mechanism. The first three hydrophobic residues of β2 are crucial for occlusion, while the remainder of the N-terminus remains flexible. Neither the closed channel conformation obtained in the absence of Ca2+ nor an intermediate conformation found in the presence of Ca2+ show density for the N-terminus of the β2 subunit in their pore, likely due to narrower side access portals preventing their entry into the channel pore. The accessory β2 subunit was proposed to inactivate BK channels via the ball-and-chain model, but structural evidence was missing. Here, using cryo-EM, the authors captured the occlusion of the BK channel pore by the N-terminus of the β2 subunit.

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