Cysteine residue 911 in C-terminal tail of human BKCaα channel subunit is crucial for its activation by carbon monoxide

Telezhkin, Vsevolod, Brazier, Stephen P., Mears, Ruth, Müller, Carsten T. ORCID: https://orcid.org/0000-0003-0455-7132, Riccardi, Daniela ORCID: https://orcid.org/0000-0002-7322-3163 and Kemp, Paul J. ORCID: https://orcid.org/0000-0003-2773-973X 2011. Cysteine residue 911 in C-terminal tail of human BKCaα channel subunit is crucial for its activation by carbon monoxide. Pflugers Archiv-European Journal of Physiology 461 (6) , pp. 665-675. 10.1007/s00424-011-0924-7

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Abstract

The large conductance, voltage- and calcium-activated potassium channel, BKCa, is a known target for the gasotransmitter, carbon monoxide (CO). Activation of BKCa by CO modulates cellular excitability and contributes to the physiology of a diverse array of processes, including vascular tone and oxygen-sensing. Currently, there is no consensus regarding the molecular mechanisms underpinning reception of CO by the BKCa. Here, employing voltage-clamped, inside-out patches from HEK293 cells expressing single, double and triple cysteine mutations in the BKCa α-subunit, we test the hypothesis that CO regulation is conferred upon the channel by interactions with cysteine residues within the RCK2 domain. In physiological [Ca2+]i, all mutants carrying a cysteine substitution at position 911 (C911G) demonstrated significantly reduced CO sensitivity; the C911G mutant did not express altered Ca2+-sensitivity. In contrast, histidine residues in RCK1 domain, previously shown to ablate CO activation in low [Ca2+]i, actually increased CO sensitivity when [Ca2+]i was in the physiological range. Importantly, cyanide, employed here as a substituent for CO at potential metal centres, occluded activation by CO; this effect was freely reversible. Taken together, these data suggest that a specific cysteine residue in the C-terminal domain, which is close to the Ca2+ bowl but which is not involved in Ca2+ activation, confers significant CO sensitivity to BKCa channels. The rapid reversibility of CO and cyanide binding, coupled to information garnered from other CO-binding proteins, suggests that C911 may be involved in formation of a transition metal cluster which can bind and, thereafter, activate BKCa.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > QP Physiology
Uncontrolled Keywords:	Potassium channel; Patch clamp; Ion channel; Electrophysiology; Calcium-activated potassium channel
Publisher:	Springer
ISSN:	0031-6768
Last Modified:	19 Oct 2022 08:40
URI:	https://orca.cardiff.ac.uk/id/eprint/18658

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