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J. Biol. Chem., Vol. 277, Issue 24, 21423-21430, June 14, 2002

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Functional Consequences of the Loss of High Affinity Agonist Binding to -Aminobutyric Acid Type A Receptors
IMPLICATIONS FOR RECEPTOR DESENSITIZATION^*

J. Glen Newell^§ and Susan M. J. Dunn^¶

From the  Department of Pharmacology and ^¶ Centre for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

We reported previously that tyrosine 62 of the 2 subunit of the -aminobutyric acid, type A (GABA_A) receptor is an important determinant of high affinity agonist binding and that recombinant 122_L receptors carrying the Y62S mutation lack measurable high affinity sites for [³H]muscimol. We have now examined the effects of disrupting these sites on the macroscopic desensitization properties of receptors expressed in Xenopus oocytes. Desensitization was measured by the ability of low concentrations of bath-perfused agonist to reduce the current responses elicited by subsequent challenges with saturating concentrations of GABA. Wild-type receptors were desensitized by pre-perfused muscimol with an IC₅₀ ~0.7 µM, which correlates well with the lower affinity sites for this agonist that are measured in direct binding studies. Receptors carrying the 2 Y62S and Y62F mutations desensitized at slightly higher (2-7-fold) agonist concentrations. However, at low perfusate concentrations, the Y62S-containing receptor recovered from the desensitized state even in the continued presence of agonist. The characteristics of desensitization in the wild-type and mutant receptors lead us to suggest that the major role of the high affinity agonist-binding site(s) of the GABA_A receptor is not to induce desensitization but rather to stabilize the desensitized state once it has been formed.

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