Fragrant Dioxane Derivatives Identify β1-Subunit-containing GABAA Receptors |
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Authors: | Olga A Sergeeva Olaf Kletke Andrea Kragler Anja Poppek Wiebke Fleischer Stephan R Schubring Boris G?rg Helmut L Haas Xin-Ran Zhu Hermann Lübbert Günter Gisselmann Hanns Hatt |
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Institution: | From the §Lehrstuhl für Zellphysiologie and ;‖Lehrstuhl für Tierphysiologie, Ruhr-Universität, 44780 Bochum, Germany and ;the ‡Institut für Neurophysiologie and ;¶Klinik für Gastroenterologie, Hepatologie, und Infektiologie, Heinrich-Heine Universität, 40001 Düsseldorf, Germany |
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Abstract: | Nineteen GABAA receptor (GABAAR) subunits are known in mammals with only a restricted number of functionally identified native combinations. The physiological role of β1-subunit-containing GABAARs is unknown. Here we report the discovery of a new structural class of GABAAR positive modulators with unique β1-subunit selectivity: fragrant dioxane derivatives (FDD). At heterologously expressed α1βxγ2L (x-for 1,2,3) GABAAR FDD were 6 times more potent at β1- versus β2- and β3-containing receptors. Serine at position 265 was essential for the high sensitivity of the β1-subunit to FDD and the β1N286W mutation nearly abolished modulation; vice versa the mutation β3N265S shifted FDD sensitivity toward the β1-type. In posterior hypothalamic neurons controlling wakefulness GABA-mediated whole-cell responses and GABAergic synaptic currents were highly sensitive to FDD, in contrast to β1-negative cerebellar Purkinje neurons. Immunostaining for the β1-subunit and the potency of FDD to modulate GABA responses in cultured hypothalamic neurons was drastically diminished by β1-siRNA treatment. In conclusion, with the help of FDDs we reveal a functional expression of β1-containing GABAARs in the hypothalamus, offering a new tool for studies on the functional diversity of native GABAARs. |
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Keywords: | GABA Receptors Neurobiology Neurochemistry Neuron Neurotransmitter Receptors Synapses |
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