Negative modulation of the GABAAρ1 receptor function by histamine

BELTRÁN GONZÁLEZ, ANDREA N.; LÓPEZ PAZOS, MANUEL I.; DEL VAS, MARIANA; CALVO, DANIEL J.

EUROPEAN JOURNAL OF PHARMACOLOGY

ELSEVIER SCIENCE BV

Año: 2023

0014-2999

Besides its function as a local mediator of the immune response, histamine can playa role as a neurotransmitter and neuromodulator. Histamine actions are classicallymediated through four different G protein-coupled receptor subtypes but non-classicalactions were also described, including effects on many ligand-gated ion channels.Previous evidence indicated that histamine acts as a positive modulator on diverseGABAA receptor subtypes, such as GABAAα1β2γ2, GABAAα2β3γ2, GABAAα3β3γ2,GABAAα4β3γ2 and GABAAα5β3γ2. Meanwhile, its effects on GABAAρ1 receptors,known to stand for tonic currents in retinal neurons, had not been examined before. Theeffects of histamine on the function of human homomeric GABAAρ1 receptors werestudied here, using heterologous expression in Xenopus laevis oocytes followed by theelectrophysiological recording of GABA-evoked Cl- currents. Histamine inhibitedGABAAρ1 receptor-mediated responses. Effects were reversible, independent of themembrane potential, and strongly dependent on both histamine and GABA concentration.A rightward parallel shift in the concentration-response curve for GABA was observedin the presence of histamine, without substantial change in the maximal response or theHill coefficient. Results were compatible with a competitive antagonism of histamine onthe GABAAρ1 receptors. This is the first report of inhibitory actions exerted by histamineon an ionotropic GABA receptor.