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An N-terminal histidine regulates Zn2+ inhibition on the murine GABAA receptor β3 subunit
Journal article   Peer reviewed

An N-terminal histidine regulates Zn2+ inhibition on the murine GABAA receptor β3 subunit

E L Dunne, A M Hosie, J R A Wooltorton, I C Duguid, K Harvey, Stephen J Moss, Robert J Harvey and T G Smart
British Journal of Pharmacology, Vol.137(1), pp.29-38
2002
DOI: https://doi.org/10.1038/sj.bjp.0704835
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https://doi.org/10.1038/sj.bjp.0704835View
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Abstract

GABAA receptor Zn2+ histidines pH b subunit N-terminal domain ion channel
1. Whole-cell currents were recorded from Xenopus laevis oocytes and human embryonic kidney cells expressing GABAA receptor β3 subunit homomers to search for additional residues affecting Zn2+ inhibition. These residues would complement the previously identified histidine (H267), present just within the external portal of the ion channel, which modulates Zn2+ inhibition. 2. Zinc inhibited the pentobarbitone-gated current on β3H267A homomers at pH 7.4, but this effect was abolished at pH 5.4. The Zn2+-sensitive spontaneous β3 subunit-mediated conductance was also insensitive to block by Zn2+ at pH 5.4. 3. Changing external pH enabled the titration of the Zn2+ sensitive binding site or signal transduction domain. The pKa was estimated at 6.8±0.03 implying the involvement of histidine residues. 4. External histidine residues in the β3 receptor subunit were substituted with alanine, in addition to the background mutation, H267A, to assess their sensitivity to Zn2+ inhibition. The Zn2+ IC50 was unaffected by either the H119A or H191A mutations. 5. The remaining histidine, H107, the only other candidate likely to participate in Zn2+ inhibition, was substituted with various residues. Most mutants were expressed at the cell surface but they disrupted functional expression of β3 homomers. However, H107G was functional and demonstrated a marked reduction in sensitivity to Zn2+. 6. GABAA receptor β3 subunits form functional ion channels that can be inhibited by Zn2+. Two histidine residues are largely responsible for this effect, H267 in the pore lining region and H107 residing in the extracellular N-terminal domain.

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