Activation mechanism and novel binding sites of the BK Ca channel activator CTIBD.

Autor: Lee N; https://ror.org/024kbgz78 School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea., Kim S; https://ror.org/024kbgz78 School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea., Lee NY; https://ror.org/024kbgz78 School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea., Jo H; https://ror.org/024kbgz78 School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea., Jeong P; Department of Chemistry, Duke University, Durham, NC, USA., Pagire HS; https://ror.org/024kbgz78 Department of Chemistry, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea., Pagire SH; https://ror.org/024kbgz78 Department of Chemistry, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea., Ahn JH; https://ror.org/024kbgz78 Department of Chemistry, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea., Jin MS; https://ror.org/024kbgz78 School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea misunjin@gist.ac.kr., Park CS; https://ror.org/024kbgz78 School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea cspark@gist.ac.kr.
Jazyk: angličtina
Zdroj: Life science alliance [Life Sci Alliance] 2024 Aug 01; Vol. 7 (10). Date of Electronic Publication: 2024 Aug 01 (Print Publication: 2024).
DOI: 10.26508/lsa.202402621
Abstrakt: The large-conductance calcium-activated potassium (BK Ca ) channel, which is crucial for urinary bladder smooth muscle relaxation, is a potential target for overactive bladder treatment. Our prior work unveiled CTIBD as a promising BK Ca channel activator, altering V 1/2 and G max This study investigates CTIBD's activation mechanism, revealing its independence from the Ca 2+ and membrane voltage sensing of the BK Ca channel. Cryo-electron microscopy disclosed that two CTIBD molecules bind to hydrophobic regions on the extracellular side of the lipid bilayer. Key residues (W22, W203, and F266) are important for CTIBD binding, and their replacement with alanine reduces CTIBD-mediated channel activation. The triple-mutant (W22A/W203A/F266A) channel showed the smallest V 1/2 shift with a minimal impact on activation and deactivation kinetics by CTIBD. At the single-channel level, CTIBD treatment was much less effective at increasing P o in the triple mutant, mainly because of a drastically increased dissociation rate compared with the WT. These findings highlight CTIBD's mechanism, offering crucial insights for developing small-molecule treatments for BK Ca -related pathophysiological conditions.
(© 2024 Lee et al.)
Databáze: MEDLINE
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