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Kinetic Determinants of Agonist Action at the Recombinant Human Glycine Receptor
Author(s) -
Lewis Trevor M.,
Schofield Peter R.,
McClellan Annette M. L.
Publication year - 2003
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2002.037796
Subject(s) - agonist , taurine , glycine , alanine , glycine receptor , chemistry , receptor , homomeric , amino acid , endocrinology , biophysics , biochemistry , biology , protein subunit , gene
The amino acids glycine, β‐alanine and taurine are all endogenous agonists of the glycine receptor. In this study, a combination of rapid agonist application onto macropatches and steady‐state single‐channel recordings was used to compare the actions of glycine, β‐alanine and taurine upon homomeric α 1 human glycine receptors transiently expressed in human embryonic kidney (HEK 293) cells. The 10–90 % rise times determined from rapid application of 100 μ m of each agonist were indistinguishable, indicating each agonist has a similar association rate. At saturating concentrations (30 m m ) the rise time for glycine (0.26 ms) was 1.8‐fold faster than that for β‐alanine (0.47 ms) and 3.9‐fold faster than that for taurine (1.01 ms), indicating clear differences in the maximum opening rate between agonists. The relaxation following rapid removal of agonist was fitted with a single exponential for β‐alanine (3.0 ms) and taurine (2.2 ms), and two exponential components for glycine with a weighted mean time constant of 27.1 ms. This was consistent with differences in dissociation rates estimated from analysis of bursts, with taurine > β‐alanine > glycine. Exponential fits to the open period distributions gave time constants that did not differ between agonists and the geometric distribution for the number of openings per burst indicated that all three agonists had a significant component of single‐opening bursts. Based upon these data, we propose a kinetic scheme with three independent open states, where the opening rates are dependent upon the activating agonist, while the closing rates are an intrinsic characteristic of the receptor.