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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., Riccardi, Daniela and Kemp, Paul J. 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: 04 Jun 2017 03:14
URI: http://orca.cf.ac.uk/id/eprint/18658

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