Laboratorio de Neurobiología Celular y Molecular, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIByNE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires (UBA), Ciudad Autónoma de Buenos Aires, Argentina.
Instituto de Agrobiotecnología y Biología Molecular (IABIMO), Instituto Nacional de Tecnología Agropecuaria (INTA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Eur J Pharmacol. 2023 Sep 15;955:175880. doi: 10.1016/j.ejphar.2023.175880. Epub 2023 Jul 3.
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 GABA receptor subtypes, such as GABAα1β2γ2, GABAα2β3γ2, GABAα3β3γ2, GABAα4β3γ2 and GABAα5β3γ2. Meanwhile, its effects on GABAρ1 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 GABAρ1 receptors were studied here, using heterologous expression in Xenopus laevis oocytes followed by the electrophysiological recording of GABA-evoked Cl currents. Histamine inhibited GABAρ1 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 GABAρ1 receptors. This is the first report of inhibitory actions exerted by histamine on an ionotropic GABA receptor.
除了作为免疫反应的局部介质外，组胺还可以作为神经递质和神经调质发挥作用。组胺的作用通过四个不同的 G 蛋白偶联受体亚型介导，但也描述了非经典作用，包括对许多配体门控离子通道的影响。先前的证据表明，组胺作为多种 GABA 受体亚型的正调节剂发挥作用，例如 GABAα1β2γ2、GABAα2β3γ2、GABAα3β3γ2、GABAα4β3γ2 和 GABAα5β3γ2。同时，其对 GABAρ1 受体的作用以前尚未研究过，GABAρ1 受体在视网膜神经元中代表紧张性电流。本文研究了组胺对人同源 GABAρ1 受体功能的影响，方法是在非洲爪蟾卵母细胞中进行异源表达，然后用电生理记录 GABA 诱导的 Cl 电流。组胺抑制 GABAρ1 受体介导的反应。作用是可逆的，与膜电位无关，并且强烈依赖于组胺和 GABA 的浓度。在存在组胺的情况下，GABA 的浓度-反应曲线向右平行移动，而最大反应或 Hill 系数没有实质性变化。结果与组胺对 GABAρ1 受体的竞争性拮抗作用一致。这是组胺对离子型 GABA 受体产生抑制作用的首次报道。
