Histamine Action on Vertebrate GABA sub(A) Receptors: DIRECT CHANNEL GATING AND POTENTIATION OF GABA RESPONSES

• Published in: The Journal of biological chemistry 2008-04, Vol.283 (16), p.10470-10475
• Main Authors: Saras, Arunesh, Gisselmann, Guenter, Vogt-Eisele, Angela K, Erlkamp, Katja S, Kletke, Olaf, Pusch, Hermann, Hatt, Hanns
• Format: Article
• Language: English
• Subjects: Xenopus
• ISSN: 0021-9258; 1083-351X

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 sub(A) receptors as potential candidates for histamine-gated channels. In Xenopus oocytes expressing homomultimeric beta channels, histamine evoked currents with an EC sub(50) of 212 mu M ( beta sub(2)) and 174 mu M ( beta sub(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 sub(1) beta sub(2) or alpha sub(1) beta sub(2) gamma sub(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 sub(2) subunit-controlled manner. Despite the vast number of synthetic modulators of GABA sub(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 sub(A) receptors and may thus represent an endogenous ligand for an allosteric site.