Campus Units

Biomedical Sciences

Document Type

Article

Publication Version

Accepted Manuscript

Publication Date

7-2015

Journal or Book Title

Molecular and Biochemical Parasitology

Volume

202

Issue

1

First Page

29

Last Page

37

DOI

10.1016/j.molbiopara.2015.09.001

Abstract

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.

Comments

This is a manuscript of an article published as MacDonald, Kevin, Michael J. Kimber, Tim A. Day, and Paula Ribeiro. "A constitutively active G protein-coupled acetylcholine receptor regulates motility of larval Schistosoma mansoni." Molecular and biochemical parasitology 202, no. 1 (2015): 29-37. doi: 10.1016/j.molbiopara.2015.09.001. Posted with permission.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Copyright Owner

Elsevier B.V.

Language

en

File Format

application/pdf

Published Version

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