title: GABAA receptors involved in sleep and anaesthesia: β1- versus β3-containing assemblies.
abstract: The histaminergic neurons of the posterior hypothalamus (tuberomamillary nucleus-TMN) control wakefulness, and their silencing through activation of GABA(A) receptors (GABA(A)R) induces sleep and is thought to mediate sedation under propofol anaesthesia. We have previously shown that the β1 subunit preferring fragrant dioxane derivatives (FDD) are highly potent modulators of GABA(A)R in TMN neurons. In recombinant receptors containing the β3N265M subunit, FDD action is abolished and GABA potency is reduced. Using rat, wild-type and β3N265M mice, FDD and propofol, we explored the relative contributions of β1- and β3-containing GABA(A)R to synaptic transmission from the GABAergic sleep-on ventrolateral preoptic area neurons to TMN. In β3N265M mice, GABA potency remained unchanged in TMN neurons, but it was decreased in cultured posterior hypothalamic neurons with impaired modulation of GABA(A)R by propofol. Spontaneous and evoked GABAergic synaptic currents (IPSC) showed β1-type pharmacology, with the same effects achieved by 3 μM propofol and 10 μM PI24513. Propofol and the FDD PI24513 suppressed neuronal firing in the majority of neurons at 5 and 100 μM, and in all cells at 10 and 250 μM, respectively. FDD given systemically in mice induced sedation but not anaesthesia. Propofol-induced currents were abolished (1-6 μM) or significantly reduced (12 μM) in β3N265M mice, whereas gating and modulation of GABA(A)R by PI24513 as well as modulation by propofol were unchanged. In conclusion, β1-containing (FDD-sensitive) GABA(A)R represent the major receptor pool in TMN neurons responding to GABA, while β3-containing (FDD-insensitive) receptors are gated by low micromolar doses of propofol. Thus, sleep and anaesthesia depend on different GABA(A)R types.
authors: Molecular Neurophysiology, Heinrich Heine University, 40001, Düsseldorf, Germany.
authors: Yevgenij
authors: Y
authors: Yanovsky
authors: Stephan
authors: S
authors: Schubring
authors: Wiebke
authors: W
authors: Fleischer
authors: Günter
authors: G
authors: Gisselmann
authors: Xin-Ran
authors: XR
authors: Zhu
authors: Hermann
authors: H
authors: Lübbert
authors: Hanns
authors: H
authors: Hatt
authors: Uwe
authors: U
authors: Rudolph
authors: Helmut L
authors: HL
authors: Haas
authors: Olga A
authors: OA
authors: Sergeeva
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000758:Anesthesia; D000818:Animals; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D015870:Gene Expression / Q000235:genetics; D006632:Histamine / Q000378:metabolism; D007026:Hypothalamic Area, Lateral / Q000166:cytology / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017354:Point Mutation / Q000502:physiology; D015742:Propofol / Q000494:pharmacology; D021122:Protein Subunits / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D012890:Sleep / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D058785:GABA-A Receptor Agonists; C546266:Gabrb1 protein, mouse; C546267:Gabrb1 protein, rat; C546270:Gabrb3 protein, mouse; C546276:Gabrb3 protein, rat; D021122:Protein Subunits; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D006632:Histamine; D015742:Propofol