Nicholl Georgina C B, Jawad Ali K, Weymouth Robert, Zhang Haoming, Beg Asim A
Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Neuroscience Program, University of Michigan, Ann Arbor, MI, USA.
Br J Pharmacol. 2017 May;174(9):781-795. doi: 10.1111/bph.13736. Epub 2017 Mar 10.
Ionotropic GABA receptors are evolutionarily conserved proteins that mediate cellular and network inhibition in both vertebrates and invertebrates. A unique class of excitatory GABA receptors has been identified in several nematode species. Despite well-characterized functions in Caenorhabditis elegans, little is known about the pharmacology of the excitatory GABA receptors EXP-1 and LGC-35. Using a panel of compounds that differentially activate and modulate ionotropic GABA receptors, we investigated the agonist binding site and allosteric modulation of EXP-1 and LGC-35.
We used two-electrode voltage clamp recordings to characterize the pharmacological profile of EXP-1 and LGC-35 receptors expressed in Xenopus laevis oocytes.
The pharmacology of EXP-1 and LGC-35 is different from that of GABA and GABA -ρ receptors. Both nematode receptors are resistant to the competitive orthosteric antagonist bicuculline and to classical ionotropic receptor pore blockers. The GABA -ρ specific antagonist, TPMPA, was the only compound tested that potently inhibited EXP-1 and LGC-35. Neurosteroids have minimal effects on GABA-induced currents, but ethanol selectively potentiates LGC-35.
The pharmacological properties of EXP-1 and LGC-35 more closely resemble the ionotropic GABA -ρ family. However, EXP-1 and LGC-35 exhibit a unique profile that differs from vertebrate GABA and GABA -ρ receptors, insect GABA receptors and nematode GABA receptors. As a pair, EXP-1 and LGC-35 may be utilized to further understand the differential molecular mechanisms of agonist, antagonist and allosteric modulation at ionotropic GABA receptors and may aid in the design of new and more specific anthelmintics that target GABA neurotransmission.
离子型GABA受体是进化上保守的蛋白质，在脊椎动物和无脊椎动物中均介导细胞和网络抑制作用。在几种线虫物种中已鉴定出一类独特的兴奋性GABA受体。尽管在秀丽隐杆线虫中其功能已得到充分表征，但关于兴奋性GABA受体EXP-1和LGC-35的药理学特性却知之甚少。我们使用一组能差异激活和调节离子型GABA受体的化合物，研究了EXP-1和LGC-35的激动剂结合位点和变构调节。
我们采用双电极电压钳记录法来表征非洲爪蟾卵母细胞中表达的EXP-1和LGC-35受体的药理学特征。
EXP-1和LGC-35的药理学特性不同于GABA和GABA-ρ受体。两种线虫受体均对竞争性正构拮抗剂荷包牡丹碱以及经典的离子型受体孔道阻滞剂具有抗性。GABA-ρ特异性拮抗剂TPMPA是唯一能有效抑制EXP-1和LGC-35的受试化合物。神经甾体对GABA诱导的电流影响极小，但乙醇可选择性增强LGC-35的作用。
EXP-1和LGC-35的药理学特性更类似于离子型GABA-ρ家族。然而，EXP-1和LGC-35表现出一种独特的特征，不同于脊椎动物的GABA和GABA-ρ受体、昆虫的GABA受体以及线虫的GABA受体。作为一对受体，EXP-1和LGC-35可用于进一步了解离子型GABA受体激动剂、拮抗剂和变构调节的不同分子机制，并可能有助于设计针对GABA神经传递的新型且更具特异性的驱虫药。
