Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Sergeeva OA, Kletke O, Kragler A, Poppek A, Fleischer W, Schubring SR, Görg B, Haas HL, Zhu XR, Lübbert H, Gisselmann G, Hatt H.
???displayArticle.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.
Bateson,
The benzodiazepine site of the GABAA receptor: an old target with new potential?
2004, Pubmed
Bateson,
The benzodiazepine site of the GABAA receptor: an old target with new potential?
2004,
Pubmed Baumann,
Forced subunit assembly in alpha1beta2gamma2 GABAA receptors. Insight into the absolute arrangement.
2002,
Pubmed
,
Xenbase Belelli,
The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid.
1997,
Pubmed
,
Xenbase Belujon,
Inhibitory transmission in locus coeruleus neurons expressing GABAA receptor epsilon subunit has a number of unique properties.
2009,
Pubmed
,
Xenbase Bencsits,
A significant part of native gamma-aminobutyric AcidA receptors containing alpha4 subunits do not contain gamma or delta subunits.
1999,
Pubmed Bonin,
GABA(A) receptor subtypes underlying general anesthesia.
2008,
Pubmed Drewe,
Synaptic transmission between dissociated adult mammalian neurons and attached synaptic boutons.
1988,
Pubmed Hill-Venning,
Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor.
1997,
Pubmed
,
Xenbase Hosie,
Zinc-mediated inhibition of GABA(A) receptors: discrete binding sites underlie subtype specificity.
2003,
Pubmed Jurd,
General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.
2003,
Pubmed Krasowski,
Propofol and other intravenous anesthetics have sites of action on the gamma-aminobutyric acid type A receptor distinct from that for isoflurane.
1998,
Pubmed Lam,
Modulatory and direct effects of propofol on recombinant GABAA receptors expressed in xenopus oocytes: influence of alpha- and gamma2-subunits.
1998,
Pubmed
,
Xenbase Li,
Expression of gamma-aminobutyric acid A receptor subunits alpha1, beta1, gamma2 mRNA in rats with hepatic encephalopathy.
2005,
Pubmed Mangan,
Cultured Hippocampal Pyramidal Neurons Express Two Kinds of GABAA Receptors.
2005,
Pubmed Meera,
Etomidate, propofol and the neurosteroid THDOC increase the GABA efficacy of recombinant alpha4beta3delta and alpha4beta3 GABA A receptors expressed in HEK cells.
2009,
Pubmed Nelson,
The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway.
2002,
Pubmed Olsen,
GABA A receptors: subtypes provide diversity of function and pharmacology.
2009,
Pubmed Olsen,
Fishing for allosteric sites on GABA(A) receptors.
2004,
Pubmed Parmentier,
Excitation of histaminergic tuberomamillary neurons by thyrotropin-releasing hormone.
2009,
Pubmed Rudolph,
GABA-based therapeutic approaches: GABAA receptor subtype functions.
2006,
Pubmed Rudolph,
Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics.
2004,
Pubmed Sergeeva,
Pharmacological properties of GABAA receptors in rat hypothalamic neurons expressing the epsilon-subunit.
2005,
Pubmed Sergeeva,
Editing of AMPA and serotonin 2C receptors in individual central neurons, controlling wakefulness.
2007,
Pubmed Sergeeva,
GABA(A) receptor heterogeneity in histaminergic neurons.
2002,
Pubmed Sergeeva,
P2Y receptor-mediated excitation in the posterior hypothalamus.
2006,
Pubmed Sherin,
Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat.
1998,
Pubmed Sherin,
Activation of ventrolateral preoptic neurons during sleep.
1996,
Pubmed Sieghart,
Subunit composition, distribution and function of GABA(A) receptor subtypes.
2002,
Pubmed Siegwart,
Molecular determinants for the action of general anesthetics at recombinant alpha(2)beta(3)gamma(2)gamma-aminobutyric acid(A) receptors.
2002,
Pubmed Sigel,
Mapping of the benzodiazepine recognition site on GABA(A) receptors.
2002,
Pubmed Thompson,
Salicylidene salicylhydrazide, a selective inhibitor of beta 1-containing GABAA receptors.
2004,
Pubmed
,
Xenbase Ueno,
Bicuculline and gabazine are allosteric inhibitors of channel opening of the GABAA receptor.
1997,
Pubmed Vorobjev,
Vibrodissociation of sliced mammalian nervous tissue.
1991,
Pubmed Wetzel,
Specificity and sensitivity of a human olfactory receptor functionally expressed in human embryonic kidney 293 cells and Xenopus Laevis oocytes.
1999,
Pubmed
,
Xenbase Wingrove,
The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit.
1994,
Pubmed
,
Xenbase Wisden,
The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon.
1992,
Pubmed Zecharia,
The involvement of hypothalamic sleep pathways in general anesthesia: testing the hypothesis using the GABAA receptor beta3N265M knock-in mouse.
2009,
Pubmed
