Premium
Molecular determinants of glycine receptor αβ subunit sensitivities to Zn 2+ ‐mediated inhibition
Author(s) -
Miller Paul S.,
Beato Marco,
Harvey Robert J.,
Smart Trevor G.
Publication year - 2005
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2005.088575
Subject(s) - glycine , protein subunit , glycine receptor , chemistry , receptor , biophysics , biochemistry , biology , amino acid , gene
Glycine receptors exhibit a biphasic sensitivity profile in response to Zn 2+ ‐mediated modulation, with low Zn 2+ concentrations potentiating (< 10 μ m ), and higher Zn 2+ concentrations inhibiting submaximal responses to glycine. Here, a substantial 30‐fold increase in sensitivity to Zn 2+ ‐mediated inhibition was apparent for the homomeric glycine receptor (GlyR) α1 subunit compared to either GlyR α2 or α3 subtypes. Swapping the divergent histidine (H107) residue in GlyR α1, which together with the conserved H109 forms part of an intersubunit Zn 2+ ‐binding site, for the equivalent asparagine residue present in GlyR α2 and α3, reversed this phenotype. Co‐expression of heteromeric GlyR α1 or α2 with the ancillary β subunit yielded receptors that maintained their distinctive sensitivities to Zn 2+ inhibition. However, GlyR α2β heteromers were consistently 2‐fold more sensitive to inhibition compared to the GlyR α2 homomer. Comparative studies to elucidate the specific residue in the β subunit responsible for this differential sensitivity revealed instead threonine 133 in the α1 subunit as a new vital component for Zn 2+ ‐mediated inhibition. Further studies on heteromeric receptors demonstrated that a mutated β subunit could indeed affect Zn 2+ ‐mediated inhibition but only from one side of the intersubunit Zn 2+ ‐binding site, equivalent to the GlyR α1 H107 face. This strongly suggests that the α subunit is responsible for Zn 2+ ‐mediated inhibition and that this is effectively transduced, asymmetrically, from the side of the Zn 2+ ‐binding site where H109 and T133 are located.