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J. Biol. Chem., Vol. 283, Issue 16, 10470-10475, April 18, 2008

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Histamine Action on Vertebrate GABA_A Receptors

DIRECT CHANNEL GATING AND POTENTIATION OF GABA RESPONSES^*

From the Lehrstuhl für Zellphysiologie, Ruhr-Universität Bochum, Universitätsstrasse 150, D-44780 Bochum, Germany

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 β subunits of GABA_A receptors as potential candidates for histamine-gated channels. In Xenopus oocytes expressing homomultimeric β channels, histamine evoked currents with an EC₅₀ of 212 µM (β₂) and 174 µM (β₃), 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 β channels a unique pharmacological profile distinct from either of these receptors. In heteromultimeric channels composed of ₁β₂ or ₁β₂₂ subunits, we found that histamine is a modulator of the GABA response rather than an agonist as it potentiates GABA-evoked currents in a 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.

Received for publication, December 7, 2007 , and in revised form, February 12, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains three supplemental figures.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 49-234-322-4106; Fax: 49-234-321-4129; E-mail: guenter.gisselmann{at}rub.de.

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