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• W2155027900 endingPage "1018" @default.
• W2155027900 startingPage "1001" @default.
• W2155027900 abstract "The onset of motor learning in rats coincides with exclusive expression of GABAA receptors containing alpha6 and delta subunits in the granule neurons of the cerebellum. This development temporally correlates with the presence of a spontaneously active chloride current through alpha6-containing GABAA receptors, known as tonic inhibition. Here we report that the coexpression of alpha6, beta2, and delta subunits produced receptor-channels which possessed two distinct and separable states of agonist affinity, one exhibiting micromolar and the other nanomolar affinities for GABA. The high-affinity state was associated with a significant level of spontaneous channel activity. Increasing the level of expression or the ratio of beta2 to alpha6 and delta subunits increased the prevalence of the high-affinity state. Comparative studies of alpha6beta2delta, alpha1beta2delta, alpha6beta2gamma2, alpha1beta2gamma2 and alpha4beta2delta receptors under equivalent levels of expression demonstrated that the significant level of spontaneous channel activity is uniquely attributable to alpha6beta2delta receptors. The pharmacology of spontaneous channel activity arising from alpha6beta2delta receptor expression corresponded to that of tonic inhibition. For example, GABAA receptor antagonists, including furosemide, blocked the spontaneous current. Further, the neuroactive steroid 5alpha-THDOC and classical glycine receptor agonists beta-alanine and taurine directly activated alpha6beta2delta receptors with high potency. Specific mutation within the GABA-dependent activation domain (betaY157F) impaired both low- and high-affinity components of GABA agonist activity in alpha6betaY157Fdelta receptors, but did not attenuate the spontaneous current. In comparison, a mutation located between the second and third transmembrane segments of the delta subunit (deltaR287M) significantly diminished the nanomolar component and the spontaneous activity. The possibility that the high affinity state of the alpha6beta2delta receptor modulates the granule neuron activity as well as potential mechanisms affecting its expression are discussed." @default.
• W2155027900 created "2016-06-24" @default.
• W2155027900 creator A5041554807 @default.
• W2155027900 creator A5064228271 @default.
• W2155027900 date "2007-06-06" @default.
• W2155027900 modified "2023-10-16" @default.
• W2155027900 title "Rat α₆β₂δ GABA_Areceptors exhibit two distinct and separable agonist affinities" @default.
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• W2155027900 doi "https://doi.org/10.1113/jphysiol.2007.132886" @default.
• W2155027900 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2170852" @default.
• W2155027900 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/17395622" @default.
• W2155027900 hasPublicationYear "2007" @default.
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