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Conformational variability of the glycine receptor M2 domain in response to activation by different agonists

Pless, Stephan A. and Dibas, Mohammed I. and Lester, Henry A. and Lynch, Joseph W. (2007) Conformational variability of the glycine receptor M2 domain in response to activation by different agonists. Journal of Biological Chemistry, 282 (49). pp. 36057-36067. ISSN 0021-9258. doi:10.1074/jbc.M706468200.

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Models describing the structural changes mediating cys-loop receptor activation generally give little attention to the possibility that different agonists may promote activation via distinct M2 pore-lining domain structural rearrangements. We investigated this question by comparing the effects of different ligands on the conformation of the external portion of the homomeric α1 glycine receptor M2 domain. Conformational flexibility was assessed by tethering a rhodamine fluorophore to cysteines introduced at the 19’ or 22’ positions and monitoring fluorescence and current changes during channel activation. During glycine activation, fluorescence of the label attached to R19’C increased by ~20% and the emission peak shifted to lower wavelengths, consistent with a more hydrophobic fluorophore environment. In contrast, ivermectin activated the receptors without producing a fluorescence change. Although taurine and β-alanine were weak partial agonists at the a1R19’C GlyR, they induced large fluorescence changes. Propofol, which drastically enhanced these currents, did not induce a glycine-like blue-shift in the spectral emission peak. The inhibitors, strychnine and picrotoxin, elicited fluorescence and current changes as expected for a competitive antagonist and an open channel blocker, respectively. Glycine and taurine (or β-alanine) also produced an increase and a decrease, respectively, in the fluorescence of a label attached to the nearby L22’C residue. Thus, results from two separate labelled residues support the conclusion that the GlyR M2 domain responds with distinct conformational changes to activation by different agonists.

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Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2007 the American Society for Biochemistry and Molecular Biology. Received for publication, August 6, 2007 , and in revised form, September 20, 2007. Originally published In Press as doi:10.1074/jbc.M706468200 on October 2, 2007. This project was supported by the National Health and Medical Research Council of Australia (NHMRC) and by the US National Institutes of Health (NS-11756). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. We thank Dr. Tim Webb for helpful discussions. [S.A.P was] [s]upported by an International Postgraduate Research Scholarship from the University of Queensland. [M.I.D. was] [s]upported by an National Research Service Award from the National Institutes of Health. [J.W.L. was] [s]upported by a National Health and Medical Research Council of Australia Senior Research Fellowship.
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National Health and Medical Research Council (NHMRC)UNSPECIFIED
University of QueenslandUNSPECIFIED
NIH Predoctoral FellowshipUNSPECIFIED
Issue or Number:49
Record Number:CaltechAUTHORS:PLEjbc07
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8982
Deposited By: Archive Administrator
Deposited On:11 Oct 2007
Last Modified:08 Nov 2021 20:54

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