An allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening
BK type Ca 2+ -activated K + channels activate in response to both voltage and Ca 2+ . The membrane-spanning voltage sensor domain (VSD) activation and Ca 2+ binding to the cytosolic tail domain (CTD) open the pore across the membrane, but the mechanisms that couple VSD activation and Ca 2+ binding...
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Published in | Nature communications Vol. 13; no. 1; pp. 1 - 13 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
09.11.2022
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | BK type Ca
2+
-activated K
+
channels activate in response to both voltage and Ca
2+
. The membrane-spanning voltage sensor domain (VSD) activation and Ca
2+
binding to the cytosolic tail domain (CTD) open the pore across the membrane, but the mechanisms that couple VSD activation and Ca
2+
binding to pore opening are not clear. Here we show that a compound, BC5, identified from in silico screening, interacts with the CTD-VSD interface and specifically modulates the Ca
2+
dependent activation mechanism. BC5 activates the channel in the absence of Ca
2+
binding but Ca
2+
binding inhibits BC5 effects. Thus, BC5 perturbs a pathway that couples Ca
2+
binding to pore opening to allosterically affect both, which is further supported by atomistic simulations and mutagenesis. The results suggest that the CTD-VSD interaction makes a major contribution to the mechanism of Ca
2+
dependent activation and is an important site for allosteric agonists to modulate BK channel activation.
Ca
2+
activated BK channels are important for neural and muscle function. Here authors use a compound, BC5, to show that the interface between the cytosolic and voltage sensing domains is a major allosteric pathway for Ca
2+
binding to open the channel. |
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ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-022-34359-6 |