Mutations affecting the glycine receptor agonist transduction mechanism convert the competitive antagonist, picrotoxin, into an allosteric potentiator

Lynch, Joseph W., Rajendra, Sundran, Barry, Peter H. and Schofield, Peter R. (1995) Mutations affecting the glycine receptor agonist transduction mechanism convert the competitive antagonist, picrotoxin, into an allosteric potentiator. Journal of Biological Chemistry, 270 23: 13799-13806. doi:10.1074/jbc.270.23.13799

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Author Lynch, Joseph W.
Rajendra, Sundran
Barry, Peter H.
Schofield, Peter R.
Title Mutations affecting the glycine receptor agonist transduction mechanism convert the competitive antagonist, picrotoxin, into an allosteric potentiator
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 1995-06
Sub-type Article (original research)
DOI 10.1074/jbc.270.23.13799
Open Access Status File (Publisher version)
Volume 270
Issue 23
Start page 13799
End page 13806
Total pages 8
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Formatted abstract
Contrary to its effects on the γ-aminobutyric acid type A receptor, picrotoxin antagonism of the α1 subunit of the human glycine receptor is shown to be competitive, not use-dependent, and nonselective between the picrotoxin components, picrotin, and picrotoxinin. Competitive antagonism and non-use dependence are consistent with picrotoxin binding to a site in the extracellular domain. The mutations Arg → Leu or Arg → Gln at residue 271 of the glycine receptor α1 subunit, which are both associated with human startle disease, have previously been demonstrated to disrupt the transduction process between agonist binding and channel activation. We show here that these mutations also transform picrotoxin from an allosterically acting competitive antagonist to an allosteric potentiator at low (0.01-3 μM) concentrations and to a noncompetitive antagonist at higher (≥3 μM) concentrations. This demonstrates that arginine 271 is involved in the transduction process between picrotoxin binding and its mechanism of action. Thus, the allosteric transduction pathways of both agonists and antagonists converge at a common residue prior to the activation gate of the channel, suggesting that this residue may act as an integration point for information from various extracellular ligand binding sites.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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