title: High constitutive activity of native H3 receptors regulates histamine neurons in brain.
abstract: Some G-protein-coupled receptors display 'constitutive activity', that is, spontaneous activity in the absence of agonist. This means that a proportion of the receptor population spontaneously undergoes an allosteric transition, leading to a conformation that can bind G proteins. The process has been shown to occur with recombinant receptors expressed at high density, and/or mutated, but also non-mutated recombinant receptors expressed at physiological concentrations. Transgenic mice that express a constitutively active mutant of the beta2-adrenergic receptor display cardiac anomalies; and spontaneous receptor mutations leading to constitutive activity are at the origin of some human diseases. Nevertheless, this process has not previously been found to occur in animals expressing normal levels of receptor. Here we show that two isoforms of the recombinant rat H3 receptor display high constitutive activity. Using drugs that abrogate this activity ('inverse agonists') and a drug that opposes both agonists and inverse agonists ('neutral antagonist'), we show that constitutive activity of native H3 receptors is present in rodent brain and that it controls histaminergic neuron activity in vivo. Inverse agonists may therefore find therapeutic applications, even in the case of diseases involving non-mutated receptors expressed at normal levels.
authors.affiliation: Unité de Neurobiologie et Pharmacologie Moléculaire (U.109) de l'INSERM, Centre Paul Broca, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Morisset
authors.forename: A
authors.initials: A
authors.lastname: Rouleau
authors.forename: X
authors.initials: X
authors.lastname: Ligneau
authors.forename: F
authors.initials: F
authors.lastname: Gbahou
authors.forename: J
authors.initials: J
authors.lastname: Tardivel-Lacombe
authors.forename: H
authors.initials: H
authors.lastname: Stark
authors.forename: W
authors.initials: W
authors.lastname: Schunack
authors.forename: C R
authors.initials: CR
authors.lastname: Ganellin
authors.forename: J C
authors.initials: JC
authors.lastname: Schwartz
authors.forename: J M
authors.initials: JM
authors.lastname: Arrang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D003001:Cloning, Molecular; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006632:Histamine / Q000378:metabolism*; D006633:Histamine Antagonists / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008024:Ligands; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: C417964:FUB 465; D006633:Histamine Antagonists; D007093:Imidazoles; D008024:Ligands; D020033:Protein Isoforms; D018100:Receptors, Histamine H3; D011994:Recombinant Proteins; C417965:proxyfan; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C115705:ciproxifan; D006632:Histamine