NDLI: Histamine action on vertebrate GABAA receptors: direct channel gating and potentiation of GABA responses.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Kletke, Olaf Pusch, Hermann Vogt-eisele, Angela K. Erlkamp, Katja S. Gisselmann, Günter Saras, Arunesh Hatt, Hanns
Description	Author Affiliation: Saras A ( Lehrstuhl für Zellphysiologie, Ruhr-Universität Bochum, Universitätsstrasse 150, D-44780 Bochum, Germany.)
Abstract	Histamine is not only a crucial cytokine in the periphery but also an important neurotransmitter and neuromodulator in the brain. It is known to act on metabotropic H1-H4 receptors, but the existence of directly histamine-gated chloride channels in mammals has been suspected for many years. However, the molecular basis of such mammalian channels remained elusive, whereas in invertebrates, genes for histamine-gated channels have been already identified. In this report, we demonstrated that histamine can directly open vertebrate ion channels and identified beta subunits of GABA(A) receptors as potential candidates for histamine-gated channels. In Xenopus oocytes expressing homomultimeric beta channels, histamine evoked currents with an EC(50) of 212 microm (beta(2)) and 174 microm (beta(3)), whereas GABA is only a very weak partial agonist. We tested several known agonists and antagonists for the histamine-binding site of H1-H4 receptors and described for beta channels a unique pharmacological profile distinct from either of these receptors. In heteromultimeric channels composed of alpha(1)beta(2) or alpha(1)beta(2)gamma(2) subunits, we found that histamine is a modulator of the GABA response rather than an agonist as it potentiates GABA-evoked currents in a gamma(2) subunit-controlled manner. Despite the vast number of synthetic modulators of GABA(A) receptors widely used in medicine, which act on several distinct sites, only a few endogenous modulators have yet been identified. We show here for the first time that histamine modulates heteromultimeric GABA(A) receptors and may thus represent an endogenous ligand for an allosteric site.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	16
Volume Number	283
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2008-04-18
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Gene Expression Regulation Histamine Metabolism Receptors, GABA-A Allosteric Site Animals Cell Line Ion Channel Gating Ligands Models, Biological Oocytes Patch-Clamp Techniques Piperidines Pharmacology Xenopus Laevis Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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