Structure-function study of the fourth transmembrane segment of the GABAρ1 receptor

Estrada-Mondragón, Argel, Reyes-Ruiz, Jorge Mauricio, Martínez-Torres, Ataúlfo and Miledia, Ricardo (2010) Structure-function study of the fourth transmembrane segment of the GABAρ1 receptor. Proceeding of the National Academy of Sciences of the United States of America, 107 41: 17780-17784. doi:10.1073/pnas.1012540107


Author Estrada-Mondragón, Argel
Reyes-Ruiz, Jorge Mauricio
Martínez-Torres, Ataúlfo
Miledia, Ricardo
Title Structure-function study of the fourth transmembrane segment of the GABAρ1 receptor
Journal name Proceeding of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2010-10-12
Sub-type Article (original research)
DOI 10.1073/pnas.1012540107
Volume 107
Issue 41
Start page 17780
End page 17784
Total pages 5
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Abstract The Cys-loop family of receptors mediates synaptic neurotransmission in the central nervous system of vertebrates. These receptors share several structural characteristics and assemble in the plasma membrane as multimers with fivefold symmetry. Of these, the ionotropic GABA receptors are key players in the pathogenesis of diseases like epilepsy, anxiety, and schizophrenia. Different experimental approaches have shed some light on the mechanisms behind the function of these receptors; but little is known about their structure at high resolution. Sequence homology with the nicotinic acetylcholine receptor predicts that ionotropic GABA receptors possess four transmembrane segments (TM1-4) and that TM2 forms the wall of the ion channel. However, the role of the other three segments is unclear. The GABAρ1 receptor plays a fundamental role in the regulation of neurotransmission along the visual pathway, is highly sensitive to GABA, and exhibits little desensitization. In our recent investigations of the role of TM4 in receptor function, a key residue in this domain (W475) was found to be involved in activation of the receptor. Here we have generated a structural model of the GABAρ1 receptor in silico and assessed its validity by electrophysiologically testing nine amino acid substitutions of W475 and deletions of the neighboring residues (Y474 and S476). The results identify a critical linkage between the ligand-binding domain and the TM4 domain and provide a framework for more detailed structure-function analyses of ionotropic GABA receptors.
Keyword Receptor structure
Two-microelectrode voltage clamp
Xenopus oocyte
In silico modeling
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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Created: Thu, 04 Sep 2014, 18:33:56 EST by Argel Estrada on behalf of Queensland Brain Institute