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J Biol Chem. 2010 Jul 30;285(31):23985-93. doi: 10.1074/jbc.M110.103309. Epub 2010 May 28.

Fragrant dioxane derivatives identify beta1-subunit-containing GABAA receptors.

Author information

1
Lehrstuhl für Zellphysiologie, Ruhr-Universität, 44780 Bochum, Germany. olga.sergeeva@uni-duesseldorf.de

Abstract

Nineteen GABA(A) receptor (GABA(A)R) subunits are known in mammals with only a restricted number of functionally identified native combinations. The physiological role of beta1-subunit-containing GABA(A)Rs is unknown. Here we report the discovery of a new structural class of GABA(A)R positive modulators with unique beta1-subunit selectivity: fragrant dioxane derivatives (FDD). At heterologously expressed alpha1betaxgamma2L (x-for 1,2,3) GABA(A)R FDD were 6 times more potent at beta1- versus beta2- and beta3-containing receptors. Serine at position 265 was essential for the high sensitivity of the beta1-subunit to FDD and the beta1N286W mutation nearly abolished modulation; vice versa the mutation beta3N265S shifted FDD sensitivity toward the beta1-type. In posterior hypothalamic neurons controlling wakefulness GABA-mediated whole-cell responses and GABAergic synaptic currents were highly sensitive to FDD, in contrast to beta1-negative cerebellar Purkinje neurons. Immunostaining for the beta1-subunit and the potency of FDD to modulate GABA responses in cultured hypothalamic neurons was drastically diminished by beta1-siRNA treatment. In conclusion, with the help of FDDs we reveal a functional expression of beta1-containing GABA(A)Rs in the hypothalamus, offering a new tool for studies on the functional diversity of native GABA(A)Rs.

PMID:
20511229
PMCID:
PMC2911342
DOI:
10.1074/jbc.M110.103309
[Indexed for MEDLINE]
Free PMC Article

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