Functional characterization of three G protein-coupled acetylcholine receptors in parasitic nematode Trichinella spiralis

• Published in: International journal for parasitology -- drugs and drug resistance Vol. 23; pp. 130 - 139
• Main Authors: Nìng, Cáinà, Heckmann, Aurélie, Mateos-Hernández, Lourdes, Karadjian, Grégory, Šimo, Ladislav
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier 01.12.2023
• Subjects: Acetylcholine - pharmacology; Animals; Calcium mobilization; CHO cell; CHO Cells; Cricetinae; Cricetulus; GAR; GTP-Binding Proteins; Humans; Infant, Newborn; Life Sciences; Microbiology and Parasitology; Muscarinic Agonists - pharmacology; Pharmacology; Phylogeny; Receptors, Cholinergic - genetics; Receptors, G-Protein-Coupled; Regular article; Trichinella; Trichinella spiralis - genetics; GAR; Calcium mobilization; Pharmacology; Trichinella; CHO cell; Calcium; mobilization
• ISSN: 2211-3207; 2211-3207
• DOI: 10.1016/j.ijpddr.2023.11.005

The physiological significance of metabotropic acetylcholine receptors in parasitic nematodes remains largely unexplored. Here, three different Trichinella spiralis G protein-coupled acetylcholine receptors (TsGAR-1, -2, and -3) were identified in the genome of T. spiralis. The phylogenetic analyses showed that TsGAR-1 and -2 receptors belong to a distinct clade specific to invertebrates, while TsGAR-3 is closest to the cluster of mammalian-type muscarinic acetylcholine receptors (mAChR). The mRNA of TsGAR-1, -2, and -3 was detected in muscle larvae, newborn larvae, and adults. The functional aequorin-based assay in Chinese hamster ovary cells revealed that all three types of T. spiralis GARs trigger the G pathway upon activation of the receptor with the acetylcholine ligand. TsGAR-1 and TsGAR-2 showed atypical affinity with classical muscarinic agonists, while TsGAR-3 was sensitive to all muscarinic agonists tested. High concentrations of propiverine antagonist blocked the activities of all three TsGARs, while atropine and scopolamine antagonists effectively inhibited only TsGAR-3. Our data indicate that the distinct pharmacological profile of TsGAR-1 and -2 receptors, as well as the phylogenetic distance between them and their mammalian orthologs, place them as attractive targets for the development of selective anthelmintic drugs interfering with nematodes' cholinergic system.