Negative modulation of the GABAρ1 receptor function by histamine

Besides its function as a local mediator of the immune response, histamine can play a role as a neurotransmitter and neuromodulator. Histamine actions are classically mediated through four different G protein-coupled receptor subtypes but non-classical actions were also described, including effects on many ligand-gated ion channels. Previous evidence indicated that histamine acts as a positive modulator on diverse GABAA receptor subtypes, such as GABAA alpha 1 beta 2 gamma 2, GABA(A)alpha 2 beta 3 gamma 2, GABA(A)alpha 3 beta 3 gamma 2, GABA(A)alpha 4 beta 3 gamma 2 and GABA(A)alpha 5 beta 3 gamma 2. Meanwhile, its effects on GABA(A)rho 1 receptors, known to stand for tonic currents in retinal neurons, had not been examined before. The effects of histamine on the function of human homomeric GABA alpha rho 1 receptors were studied here, using heterologous expression in Xenopus laevis oocytes followed by the electrophysiological recording of GABAevoked Cl- currents. Histamine inhibited GABAA.1 receptor-mediated responses. Effects were reversible, independent of the membrane potential, and strongly dependent on both histamine and GABA concentration. A rightward parallel shift in the concentration-response curve for GABA was observed in the presence of histamine, without substantial change in the maximal response or the Hill coefficient. Results were compatible with a competitive antagonism of histamine on the GABA(A rho)1 receptors. This is the first report of inhibitory actions exerted by histamine on an ionotropic GABA receptor.