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

Chen, Xuebin, Cromer, Brett, Webb, Timothy I., Yang, Zhe, Hantke, Janina, Harvey, Robert J., Parker, Michael W. and Lynch, Joseph W. (2009) Dihydropyridine inhibition of the glycine receptor: Subunit selectivity and a molecular determinant of inhibition. Neuropharmacology, 56 1: 318-327. doi:10.1016/j.neuropharm.2008.07.001


Author Chen, Xuebin
Cromer, Brett
Webb, Timothy I.
Yang, Zhe
Hantke, Janina
Harvey, Robert J.
Parker, Michael W.
Lynch, Joseph W.
Title Dihydropyridine inhibition of the glycine receptor: Subunit selectivity and a molecular determinant of inhibition
Journal name Neuropharmacology   Check publisher's open access policy
ISSN 0028-3908
1873-7064
Publication date 2009-01-01
Year available 2008
Sub-type Article (original research)
DOI 10.1016/j.neuropharm.2008.07.001
Open Access Status Not Open Access
Volume 56
Issue 1
Start page 318
End page 327
Total pages 10
Editor Graham L. Collingridge
Place of publication London, England
Publisher Pergamon
Language eng
Subject C1
110902 Cellular Nervous System
110904 Neurology and Neuromuscular Diseases
920111 Nervous System and Disorders
Abstract 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 G2′A 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.
Keyword Nifedipine
Nicardipine
Cys-loop receptor
Chloride channel
Inhibitory neurotransmission
Binding site
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID G0500833
G0500833(74778)
Institutional Status UQ
Additional Notes Available online 9 July 2008.

 
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Created: Wed, 15 Apr 2009, 00:21:38 EST by Debra McMurtrie on behalf of Queensland Brain Institute