Negative modulation of the GAB(A)rho 1 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.

Automated summary

Histamine can function as a neurotransmitter and neuromodulator in addition to its role as a mediator of the immune response. It was previously shown to act as a positive modulator on various GABAA receptor subtypes, but its effects on GABA(A)rho 1 receptors had not been studied. This research demonstrated that histamine inhibits GABAA.1 receptor-mediated responses through competitive antagonism on GABA(A rho)1 receptors.