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Selective block of the human 2-P domain potassium channel, TASK-3, and the native leak potassium current, IKSO, by zinc.

Clarke, Catherine E, Veale, Emma L., Green, Paula J, Meadows, Helen J, Mathie, Alistair (2004) Selective block of the human 2-P domain potassium channel, TASK-3, and the native leak potassium current, IKSO, by zinc. The Journal of physiology, 560 (Pt 1). pp. 51-62. ISSN 0022-3751. (doi:10.1113/jphysiol.2004.070292) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:75931)

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http://dx.doi.org/10.1113/jphysiol.2004.070292

Abstract

Background potassium channels control the resting membrane potential of neurones and regulate their excitability. Two-pore-domain potassium (2-PK) channels have been shown to underlie a number of such neuronal background currents. Currents through human TASK-1, TASK-2 and TASK-3 channels expressed in Xenopus oocytes were inhibited by extracellular acidification. For TASK-3, mutation of histidine 98 to aspartate or alanine considerably reduced this effect of pH. Zinc was found to be a selective blocker of TASK-3 with virtually no effect on TASK-1 or TASK-2. Zinc had an IC(50) of 19.8 microM for TASK-3, at +80 mV, with little voltage dependence associated with this inhibition. TASK-3 H98A had a much reduced sensitivity to zinc suggesting this site is important for zinc block. Surprisingly, TASK-1 also has histidine in position 98 but is insensitive to zinc block. TASK-3 and TASK-1 differ at position 70 with glutamate for TASK-3 and lysine for TASK-1. TASK-3 E70K also had a much reduced sensitivity to zinc while the corresponding reverse mutation in TASK-1, K70E, induced zinc sensitivity. A TASK-3-TASK-1 concatamer channel was comparatively zinc insensitive. For TASK-3, it is concluded that positions E70 and H98 are both critical for zinc block. The native cerebellar granule neurone (CGN) leak current, IK(SO), is sensitive to block by zinc, with current reduced to 0.58 of control values in the presence of 100 microM zinc. This suggests that TASK-3 channels underlie a major component of IK(SO). It has recently been suggested that zinc is released from inhibitory synapses onto CGNs. Therefore it is possible that inhibition of IK(SO) in cerebellar granule cells by synaptically released zinc may have important physiological consequences.

Item Type: Article
DOI/Identification number: 10.1113/jphysiol.2004.070292
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Emma Veale
Date Deposited: 21 Aug 2019 12:20 UTC
Last Modified: 23 Jan 2020 04:16 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/75931 (The current URI for this page, for reference purposes)
Veale, Emma L.: https://orcid.org/0000-0002-6778-9929
Mathie, Alistair: https://orcid.org/0000-0001-6094-2890
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