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Zinc Potentiation of the Glycine Receptor Chloride Channel Is Mediated by Allosteric Pathways
Author(s) -
Lynch Joseph W.,
Jacques Patrice,
Pierce Kerrie D.,
Schofield Peter R.
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.71052159.x
Subject(s) - allosteric regulation , long term potentiation , glycine , glycine receptor , chemistry , chloride channel , receptor , biochemistry , zinc , neuroscience , biophysics , pharmacology , microbiology and biotechnology , biology , amino acid , organic chemistry
Molecular mechanisms of zinc potentiation were investigated in recombinant human α1 glycine receptors (GlyRs) by whole‐cell patch‐clamp recording and [ 3 H]strychnine binding assays. In the wild‐type (WT) GlyR, 1 µ M zinc enhanced the apparent binding affinity of the agonists glycine and taurine and reduced their concentrations required for half‐maximal activation. Thus, in the WT GlyR, zinc potentiation apparently occurs by enhancing agonist binding. However, analysis of GlyRs incorporating mutations in the membrane‐spanning domain M1–M2 and M2–M3 loops, which are both components of the agonist gating mechanism, indicates that most mutations uncoupled zinc potentiation from glycine‐gated currents but preserved zinc potentiation of taurine‐gated currents. One such mutation in the M2–M3 loop, L274A, abolished the ability of zinc to potentiate taurine binding but did not inhibit zinc potentiation of taurine‐gated currents. In this same mutant where taurine acts as a partial agonist, zinc potentiated taurine‐gated currents but did not potentiate taurine antagonism of glycine‐gated currents, suggesting that zinc interacts selectively with the agonist transduction pathway. The intracellular M246A mutation, which is unlikely to bind zinc, also disrupted zinc potentiation of glycine currents. Thus, zinc potentiation of the GlyR is mediated via allosteric mechanisms that are independent of its effects on agonist binding.