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Received June 17, 2004
Revised July 9, 2004
Accepted after revision July 22, 2004
1 Imperial College London
2 GlaxoSmithKline
* To whom correspondence should be addressed. E-mail: a.mathie{at}imperial.ac.uk.
Background potassium channels control the resting membrane potential of neurons 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 IC50 of 19.8 µM 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 neuron (CGN) leak current, IKSO, is sensitive to block by zinc, with current reduced to 0.58 of control values in the presence of 100 µM zinc. This suggests that TASK-3 channels underlie a major component of IKSO. It has recently been suggested that zinc is released from inhibitory synapses onto CGNs. Therefore it is possible that inhibition of IKSO in cerebellar granule cells by synaptically released zinc may have important physiological consequences.
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