Dihydropyridine inhibition of the glycine receptor: Subunit selectivity and a molecular determinant of inhibition

X Chen; B Cromer; T I Webb; Z Yang; J Hantke; Robert J Harvey; M W Parker; J W Lynch

doi:10.1016/j.neuropharm.2008.07.001

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Dihydropyridine inhibition of the glycine receptor: Subunit selectivity and a molecular determinant of inhibition

Journal article

Peer reviewed

Dihydropyridine inhibition of the glycine receptor: Subunit selectivity and a molecular determinant of inhibition

X Chen, B Cromer, T I Webb, Z Yang, J Hantke, Robert J Harvey, M W Parker and J W Lynch

Neuropharmacology, Vol.56(1), pp.318-327

2009

DOI: https://doi.org/10.1016/j.neuropharm.2008.07.001

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Abstract

nifedipine

nicardipine

cys-loop receptor

chloride channel

inhibitory neurotransmission

binding site

The dihydropyridines (DHPs), nifedipine and nicardipine, modulate native glycine receptors (GlyRs) at micromolar concentrations. Nicardipine has a biphasic potentiating and inhibitory effect, whereas nifedipine causes inhibition only. The present study sought to investigate (1) the molecular mechanism by which these compounds inhibit recombinant GlyRs, and (2) their potential utility as subunit-selective inhibitors of α1, α1β, α3 and α3β GlyRs. The rate of onset of inhibition in the open state was accelerated by pre-application of DHP in the closed state, with the degree of acceleration proportional to the concentration of pre-applied DHP. This implies a non-inhibitory binding site close to the DHP inhibitory site. DHP inhibition was use-dependent and independent of glycine concentration, consistent with a pore-blocking mode of action. DHP sensitivity was abolished by the G2â€²A mutation, providing a strong case for a DHP binding site in the pore. Nifedipine exhibited an approximately 10-fold higher inhibitory potency at α1-containing relative to α3-containing receptors, whereas nicardipine was only weakly selective for α1-containing GlyRs. The differential sensitivities of nifedipine and nicardipine for different GlyR isoforms suggest that DHPs may be a useful resource to screen as pharmacological tools for selectively inhibiting different synaptic GlyR isoforms. © 2008 Elsevier Ltd. All rights reserved.

Details

Title: Dihydropyridine inhibition of the glycine receptor: Subunit selectivity and a molecular determinant of inhibition
Authors: X Chen (Author) - University of Queensland
B Cromer (Author) - University of Melbourne
T I Webb (Author) - University of Queensland
Z Yang (Author) - University of Queensland
J Hantke (Author) - University College London, United Kingdom
Robert J Harvey (Author) - University College London, United Kingdom
M W Parker (Author) - St. Vincent's Institute of Medical Research
J W Lynch (Author) - University of Queensland
Publication details: Neuropharmacology, Vol.56(1), pp.318-327
Publisher: Pergamon
Date published: 2009
DOI: 10.1016/j.neuropharm.2008.07.001
ISSN: 0028-3908
Organisation Unit: School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99451054302621
Output Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Neurosciences; Pharmacology & Pharmacy

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