Nematode cys-loop GABA receptors: biological function, pharmacology and sites of action for anthelmintics

Abstract

Parasitic nematode infection of humans and livestock is a major problem globally. Attempts to control nematode populations have led to the development of several classes of anthelmintic, which target cys-loop ligand-gated ion channels. Unlike the vertebrate nervous system, the nematode nervous system possesses a large and diversified array of ligand-gated chloride channels that comprise key components of the inhibitory neurotransmission system. In particular, cys-loop GABA receptors have evolved to play many fundamental roles in nematode behaviour such as locomotion. Analysis of the genomes of several free-living and parasitic nematodes suggests that there are several groups of cys-loop GABA receptor subunits that, for the most part, are conserved among nematodes. Despite many similarities with vertebrate cys-loop GABA receptors, those in nematodes are quite distinct in sequence similarity, subunit composition and biological function. With rising anthelmintic resistance in many nematode populations worldwide, GABA receptors should become an area of increased scientific investigation in the development of the next generation of anthelmintics.

Ion Channels and Drug Transporters as Targets for Anthelmintics

“…GABA-gated chloride channels are ligand (GABA)-gated inhibitory channels that mediate the relaxation phase of nematode sinusoidal muscle movement [reviewed in 57]. GABA channel agonists such as the anthelmintic piperazine act on this channel to produce flaccid paralysis of the worm [58].…”

Actions of Agonists, Fipronil and Ivermectin on the Predominant In Vivo Splice and Edit Variant (RDLbd, I/V) of the Drosophila GABA Receptor Expressed in Xenopus laevis Oocytes

“…This is due to several factors. First, they are widely distributed throughout the nervous systems of vertebrates [1], [2] and invertebrates [3]–[5]. Secondly, they are the targets of a large number of diverse drugs, including anxiolytic and anticonvulsant benzodiazepines [6] as well as anaesthetics such as propofol [7] and steroids [8].…”

Hco-LGC-38 is novel nematode cys-loop GABA receptor subunit

“…In contrast, insect RDL receptors are thought to be involved in promoting sleep [31], as well as processing olfactory, visual and mechanosensory information [32]. The lgc-38 gene appears to be present in the genomes of all nematodes for which there is genome sequence data available [10]. These include C. elegans, B. malayai, A. suum, Trichinella spiralis and Loa loa.…”

“…The neurotransmitter GABA has been detected in motor neuron commissures in H. contortus [17] which suggests that some of the receptors for GABA could be involved in movement in parasitic nematodes. In fact, another GABA receptor LGC-37 has been localized to the ventral nerve cord (sites of neuromuscular junctions) in H. contortus [33] and it is well established that ionotropic GABA receptors are present in the body muscle of Ascaris [10] further supporting the role of GABA receptors in somatic muscle contraction in parasitic nematodes. Overall, Hco-LGC-38 did not produce large currents in oocytes, which may indicate that other subunits or accessory proteins may play a role in its function.…”

“…genes appear conserved among nematodes across several clades [10]. These subunits include UNC-49B/C and GAB-1 which have been isolated from C. elegans and found to form GABA-gated chloride channels when expressed in Xenopus oocytes [11,12].…”