Functional consequences of the loss of high affinity agonist binding to gamma-aminobutyric acid type A receptors. Implications for receptor desensitization

The Journal of Biological Chemistry
J Glen Newell, Susan M J Dunn

Abstract

We reported previously that tyrosine 62 of the beta2 subunit of the gamma-aminobutyric acid, type A (GABA(A)) receptor is an important determinant of high affinity agonist binding and that recombinant alpha1beta2gamma2(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 approximately 0.7 microm, which correlates well with the lower affinity sites for this agonist that are measured in direct binding studies. Receptors carrying the beta2 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 ...Continue Reading

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Citations

Sep 27, 2003·Journal of Neurochemistry·Roland Baur, Erwin Sigel
Sep 1, 2005·European Journal of Pharmacology·Reena S HansenMartin Davies
Dec 20, 2018·Journal of Neurochemistry·Ali Y BenkheroufMikko Uusi-Oukari
Sep 27, 2002·The Journal of Biological Chemistry·Sabine W BaumannErwin Sigel
Jul 26, 2017·Scientific Reports·Cecilia M BorgheseBoris Tabakoff

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