{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T12:59:38Z","timestamp":1778936378705,"version":"3.51.4"},"reference-count":72,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2007,6,6]],"date-time":"2007-06-06T00:00:00Z","timestamp":1181088000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2007,6,15]]},"abstract":"<jats:p>The onset of motor learning in rats coincides with exclusive expression of GABA<jats:sub>A<\/jats:sub>receptors containing \u03b1<jats:sub>6<\/jats:sub>and \u03b4 subunits in the granule neurons of the cerebellum. This development temporally correlates with the presence of a spontaneously active chloride current through \u03b1<jats:sub>6<\/jats:sub>\u2010containing GABA<jats:sub>A<\/jats:sub>receptors, known as tonic inhibition. Here we report that the coexpression of \u03b1<jats:sub>6<\/jats:sub>, \u03b2<jats:sub>2<\/jats:sub>, and \u03b4 subunits produced receptor\u2013channels which possessed two distinct and separable states of agonist affinity, one exhibiting micromolar and the other nanomolar affinities for GABA. The high\u2010affinity state was associated with a significant level of spontaneous channel activity. Increasing the level of expression or the ratio of \u03b2<jats:sub>2<\/jats:sub>to \u03b1<jats:sub>6<\/jats:sub>and \u03b4 subunits increased the prevalence of the high\u2010affinity state. Comparative studies of \u03b1<jats:sub>6<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>\u03b4, \u03b1<jats:sub>1<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>\u03b4, \u03b1<jats:sub>6<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>\u03b3<jats:sub>2<\/jats:sub>, \u03b1<jats:sub>1<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>\u03b3<jats:sub>2<\/jats:sub>and \u03b1<jats:sub>4<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>\u03b4 receptors under equivalent levels of expression demonstrated that the significant level of spontaneous channel activity is uniquely attributable to \u03b1<jats:sub>6<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>\u03b4 receptors. The pharmacology of spontaneous channel activity arising from \u03b1<jats:sub>6<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>\u03b4 receptor expression corresponded to that of tonic inhibition. For example, GABA<jats:sub>A<\/jats:sub>receptor antagonists, including furosemide, blocked the spontaneous current. Further, the neuroactive steroid 5\u03b1\u2010THDOC and classical glycine receptor agonists \u03b2\u2010alanine and taurine directly activated \u03b1<jats:sub>6<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>\u03b4 receptors with high potency. Specific mutation within the GABA\u2010dependent activation domain (\u03b2<jats:sup>Y157F<\/jats:sup>) impaired both low\u2010 and high\u2010affinity components of GABA agonist activity in \u03b1<jats:sub>6<\/jats:sub>\u03b2<jats:sup>Y157F<\/jats:sup>\u03b4 receptors, but did not attenuate the spontaneous current. In comparison, a mutation located between the second and third transmembrane segments of the \u03b4 subunit (\u03b4<jats:sup>R287M<\/jats:sup>) significantly diminished the nanomolar component and the spontaneous activity. The possibility that the high affinity state of the \u03b1<jats:sub>6<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>\u03b4 receptor modulates the granule neuron activity as well as potential mechanisms affecting its expression are discussed.<\/jats:p>","DOI":"10.1113\/jphysiol.2007.132886","type":"journal-article","created":{"date-parts":[[2007,3,30]],"date-time":"2007-03-30T00:35:00Z","timestamp":1175214900000},"page":"1001-1018","source":"Crossref","is-referenced-by-count":51,"title":["Rat \u03b1<sub>6<\/sub>\u03b2<sub>2<\/sub>\u03b4 GABA<sub>A<\/sub>receptors exhibit two distinct and separable agonist affinities"],"prefix":"10.1113","volume":"581","author":[{"given":"Stephen H.","family":"Hadley","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jahanshah","family":"Amin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2007,6,6]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S0026-895X(24)12165-7","article-title":"A single hydrophobic residue confers barbiturate sensitivity to \u03b3\u2010aminobutyric acid type C receptor","volume":"55","author":"Amin J","year":"1999","journal-title":"Mol Pharmacol"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/366565a0"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.1996.0042"},{"key":"e_1_2_5_5_1","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/ng0501-46","article-title":"First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the \u03b32\u2010subunit gene","volume":"28","author":"Baulac S","year":"2001","journal-title":"Nat Genet"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M105240200"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1703"},{"key":"e_1_2_5_8_1","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/S0031-6997(24)01363-2","article-title":"International Union of Pharmacology XV. 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