Stoichiometry of a pore mutation that abolishes picrotoxin-mediated antagonism of the GABAA receptor

Anna Sedelnikova, Brian E. Erkkila, Holly Harris, Stanislav O. Zakharkin, David S. Weiss

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Picrotoxin, a potent antagonist of the inhibitory central nervous system GABAA and glycine receptors, is believed to interact with residues that line the central ion pore. These pore-lining residues are in the second transmembrane domain (TM2) of each of the five constituent subunits. One of these amino acids, a threonine at the 6′ location, when mutated to phenylalanine, abolishes picrotoxin sensitivity. It has been suggested that this threonine, via hydrogen bonding, directly interacts with the picrotoxin molecule. We previously demonstrated that this mutation, in the α, β or γ subunit, can impart picrotoxin resistance to the GABA receptor. Since the functional pentameric GABA receptor contains two α subunits, two β subunits and one γ subunit, it is not clear how many α and β subunits must carry this mutation to impart the resistant phenotype. In this study, by coexpression of mutant α or β subunits with their wild-type counterparts in various defined ratios, we demonstrate that any single subunit carrying the 6′ mutation imparts picrotoxin resistance. Implications of this finding in terms of the mechanism of antagonism are considered.

Original languageEnglish (US)
Pages (from-to)569-577
Number of pages9
JournalJournal of Physiology
Volume577
Issue number2
DOIs
StatePublished - Dec 1 2006

ASJC Scopus subject areas

  • Physiology

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