A constitutively active G protein-coupled acetylcholine receptor regulates motility of larval Schistosoma mansoni

作者：MacDonald Kevin; Kimber Michael J; Day Tim A; Ribeiro Paula^*

来源：Molecular and Biochemical Parasitology, 2015, 202(1): 29-37.

DOI：10.1016/j.molbiopara.2015.09.001

• Schistosome
• G protein-coupled receptor (GPCR)
• Constitutive activity
• Acetylcholine (ACh)
• G protein-coupled acetylcholine receptor (GAR)
• RNA interference (RNAi)

The neuromuscular system of helminths controls a variety of essential biological processes and therefore represents a good source of novel drug targets. The neuroactive substance, acetylcholine controls movement of Schistosoma mansoni but the mode of action is poorly understood. Here, we present first evidence of a functional G protein-coupled acetylcholine receptor in S. mansoni, which we have named SmGAR. A bioinformatics analysis indicated that SmGAR belongs to a clade of invertebrate GAR-like receptors and is related to vertebrate muscarinic acetylcholine receptors. Functional expression studies in yeast showed that SmGAR is constitutively active but can be further activated by acetylcholine and, to a lesser extent, the cholinergic agonist, carbachol. Anti-cholinergic drugs, atropine and promethazine, were found to have inverse agonist activity towards SmGAR, causing a significant decrease in the receptor's basal activity. An RNAi phenotypic assay revealed that suppression of SmGAR activity in early-stage larval schistosomulae leads to a drastic reduction in larval motility. In sum, our results provide the first molecular evidence that cholinergic GAR-like receptors are present in schistosomes and are required for proper motor control in the larvae. The results further identify SmGAR as a possible candidate for antiparasitic drug targeting.

• 出版日期2015-7
• 单位McGill