Fragrant dioxane derivatives identify beta1-subunit-containing GABAA receptors.
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.
Lehrstuhl für Zellphysiologie, Ruhr-Universität, 44780 Bochum, Germany. olga.sergeeva@uni-duesseldorf.de
Olga A
OA
Sergeeva
Olaf
O
Kletke
Andrea
A
Kragler
Anja
A
Poppek
Wiebke
W
Fleischer
Stephan R
SR
Schubring
Boris
B
Görg
Helmut L
HL
Haas
Xin-Ran
XR
Zhu
Hermann
H
Lübbert
Günter
G
Gisselmann
Hanns
H
Hatt
D000818:Animals; D004146:Dioxanes / Q000737:chemistry*; D004594:Electrophysiology / Q000379:methods; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D051379:Mice; D009448:Neurochemistry / Q000379:methods; D009474:Neurons / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011689:Purkinje Cells / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000737:chemistry*; D014982:Xenopus laevis
D004146:Dioxanes; D034741:RNA, Small Interfering; D011963:Receptors, GABA-A