Journal article
Molecular determinants of glycine receptor αβ subunit sensitivities to Zn2+-mediated inhibition
Journal of Physiology, Vol.566(3), pp.657-670
2005
Abstract
Glycine receptors exhibit a biphasic sensitivity profile in response to Zn2+-mediated modulation, with low Zn2+ concentrations potentiating (< 10 μM), and higher Zn2+ concentrations inhibiting submaximal responses to glycine. Here, a substantial 30-fold increase in sensitivity to Zn2+-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 Zn2+-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 Zn2+ 21 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 Zn2+-mediated inhibition. Further studies on heteromeric receptors demonstrated that a mutated β subunit could indeed affect Zn2+-mediated inhibition but only from one side of the intersubunit Zn2+-binding site, equivalent to the GlyR α1 H107 face. This strongly suggests that the α subunit is responsible for Zn2+-mediated inhibition and that this is effectively transduced, asymmetrically, from the side of the Zn2+-binding site where H109 and T133 are located. © The Physiological Society 2005.
Details
- Title
- Molecular determinants of glycine receptor αβ subunit sensitivities to Zn2+-mediated inhibition
- Authors
- P S Miller (Author) - University College London, United KingdomM Beato (Author) - University College London, United KingdomRobert J Harvey (Author) - UCL School of Pharmacy, United KingdomT G Smart (Author) - University College London, United Kingdom
- Publication details
- Journal of Physiology, Vol.566(3), pp.657-670
- Publisher
- Wiley-Blackwell Publishing Ltd.
- DOI
- 10.1113/jphysiol.2005.088575
- ISSN
- 0022-3751
- Organisation Unit
- School of Health and Sport Sciences - Legacy; School of Health and Behavioural Sciences - Legacy; University of the Sunshine Coast, Queensland; Centre for Bioinnovation; School of Health
- Language
- English
- Record Identifier
- 99451043702621
- Output Type
- Journal article
Metrics
323 Record Views
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Web Of Science research areas
- Neurosciences
- Physiology
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
Source: InCites