Characterization of the antagonistic actions of histamine on homomeric GABAArho1 receptors

Abstract

Histamine may exert its effects not only through its canonical (G-protein coupled) receptors, but also by other mechanisms which are currently being studied. It was shown that histamine can modulate the activity of different ligand-gated ion channels including several subtypes of GABAA receptors. For example, it gates homomeric GABAAβ2-3 and acts as a positive modulator on heteromeric GABAAα1-5β2γ2 receptors, but its effects on GABAAρ1 receptors had never been studied before. We previously reported that histamine inhibited GABAAρ1 receptor responses in a dose-dependent, reversible and voltage-independent manner. This was the first evidence of histamine mediating an inhibitory action on a ionotropic GABA receptor and contributed to explore the role of histamine in the retina. In the present study we analyzed the mechanism of action involved in this modulation. GABAAρ1 receptors were expressed in Xenopus laevis oocytes and GABA-evoked chloride currents recorded by two-electrode voltage-clamp. Dose-response curves for GABA performed in the presence of histamine were shifted to the right, with no changes in the slope, nHill or maximum response. No use dependent effects were observed. These results are compatible with a competitive antagonism operating on the GABAAρ1 receptors. Computational docking studies and single-oocyte binding assays with tritiated GABA are being conducted to confirm the mechanism of action proposed here.