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Rat α 6 β 2 δ GABA A receptors exhibit two distinct and separable agonist affinities
Author(s) -
Hadley Stephen H.,
Amin Jahanshah
Publication year - 2007
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.2007.132886
Subject(s) - receptor , agonist , gabaa receptor , intrinsic activity , chemistry , endocrinology , medicine , biology , biochemistry , biophysics
The onset of motor learning in rats coincides with exclusive expression of GABA A receptors containing α 6 and δ subunits in the granule neurons of the cerebellum. This development temporally correlates with the presence of a spontaneously active chloride current through α 6 ‐containing GABA A receptors, known as tonic inhibition. Here we report that the coexpression of α 6 , β 2 , and δ 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 β 2 to α 6 and δ subunits increased the prevalence of the high‐affinity state. Comparative studies of α 6 β 2 δ, α 1 β 2 δ, α 6 β 2 γ 2 , α 1 β 2 γ 2 and α 4 β 2 δ receptors under equivalent levels of expression demonstrated that the significant level of spontaneous channel activity is uniquely attributable to α 6 β 2 δ receptors. The pharmacology of spontaneous channel activity arising from α 6 β 2 δ receptor expression corresponded to that of tonic inhibition. For example, GABA A receptor antagonists, including furosemide, blocked the spontaneous current. Further, the neuroactive steroid 5α‐THDOC and classical glycine receptor agonists β‐alanine and taurine directly activated α 6 β 2 δ receptors with high potency. Specific mutation within the GABA‐dependent activation domain (β Y157F ) impaired both low‐ and high‐affinity components of GABA agonist activity in α 6 β Y157F δ receptors, but did not attenuate the spontaneous current. In comparison, a mutation located between the second and third transmembrane segments of the δ subunit (δ R287M ) significantly diminished the nanomolar component and the spontaneous activity. The possibility that the high affinity state of the α 6 β 2 δ receptor modulates the granule neuron activity as well as potential mechanisms affecting its expression are discussed.