Tropisetron modulation of the glycine receptor: femtomolar potentiation and a molecular determinant of inhibition

Yang, Zhe, Ney, Agnieszka, Cromer, Brett A., Ng, Hooi-Ling, Parker, Michael W. and Lynch, Joseph W. (2007) Tropisetron modulation of the glycine receptor: femtomolar potentiation and a molecular determinant of inhibition. Journal of Neurochemistry, 100 3: 758-769. doi:10.1111/j.1471-4159.2006.04242.x


Author Yang, Zhe
Ney, Agnieszka
Cromer, Brett A.
Ng, Hooi-Ling
Parker, Michael W.
Lynch, Joseph W.
Title Tropisetron modulation of the glycine receptor: femtomolar potentiation and a molecular determinant of inhibition
Journal name Journal of Neurochemistry   Check publisher's open access policy
ISSN 0022-3042
Publication date 2007-02-01
Year available 2007
Sub-type Article (original research)
DOI 10.1111/j.1471-4159.2006.04242.x
Open Access Status Not yet assessed
Volume 100
Issue 3
Start page 758
End page 769
Total pages 12
Editor A. J. Turner
B. Collier
Place of publication Oxford, England
Publisher Blackwell Publishing
Language eng
Subject 670402 Diagnostics
C1
270104 Membrane Biology
Abstract The 5-hydroxytryptamine type-3 receptor antagonist tropisetron is in clinical use as an anti-emetic drug. This compound also exerts both potentiating and inhibitory effects on the glycine receptor chloride channel. The inhibitory effects occur at micromolar concentrations, whereas the potentiating effects are shown here to occur at femtomolar concentrations at the homomeric alpha 1 receptor. Potentiation occurred only when tropisetron was applied in the presence of glycine. We also sought to identify molecular determinants of tropisetron inhibition at the alpha 1 glycine receptor by serially mutating residues located in or near known ligand-binding sites. We discovered that conservative mutations to N102 ablated tropisetron inhibition without affecting the magnitude or sensitivity of tropisetron potentiation. Several lines of evidence, including a structure-activity analysis of tropisetron, atropine and SB203186, suggest that N102 may bind to the tropisetron tropane nitrogen via H-bonding. Mutation of the N125 residue in the beta subunit, which corresponds to N102 in the alpha 1 subunit, had little effect on tropisetron inhibitory potency. These results show that N102 is required for tropisetron inhibition but not potentiation and that inhibitory tropisetron binds in different orientations at different subunit interfaces. To our knowledge, tropisetron is the most exquisitely sensitive modulator yet identified for a cys-loop receptor.
Formatted abstract
 The 5-hydroxytryptamine type-3 receptor antagonist tropisetron is in clinical use as an anti-emetic drug. This compound also exerts both potentiating and inhibitory effects on the glycine receptor chloride channel. The inhibitory effects occur at micromolar concentrations, whereas the potentiating effects are shown here to occur at femtomolar concentrations at the homomeric α1 receptor. Potentiation occurred only when tropisetron was applied in the presence of glycine. We also sought to identify molecular determinants of tropisetron inhibition at the α1 glycine receptor by serially mutating residues located in or near known ligand-binding sites. We discovered that conservative mutations to N102 ablated tropisetron inhibition without affecting the magnitude or sensitivity of tropisetron potentiation. Several lines of evidence, including a structure-activity analysis of tropisetron, atropine and SB203186, suggest that N102 may bind to the tropisetron tropane nitrogen via H-bonding. Mutation of the N125 residue in the β subunit, which corresponds to N102 in the α1 subunit, had little effect on tropisetron inhibitory potency. These results show that N102 is required for tropisetron inhibition but not potentiation and that inhibitory tropisetron binds in different orientations at different subunit interfaces. To our knowledge, tropisetron is the most exquisitely sensitive modulator yet identified for a cys-loop receptor.
Keyword Biochemistry & Molecular Biology
Neurosciences
5-HT3 receptor antagonist
binding site
cys-loop receptor
femtomolar
ligand-gated ion channel
molecular structure and function
tropeine
Ligand-binding Domain
Rat Spinal Neurons
5-ht3 Receptor
Allosteric Modulation
Al Subunit
Site
Antagonists
Responses
Channel
Identification
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Tue, 19 Feb 2008, 02:02:13 EST