Pharmacological Profiling of a Brugia malayi Muscarinic Acetylcholine Receptor as a Putative Antiparasitic Target

Abstract

The diversification of anthelmintic targets and mechanisms of action will help ensure the sustainable control of nematode infections in response to the growing threat of drug resistance. G protein-coupled receptors (GPCRs) are established drug targets in human medicine but remain unexploited as anthelmintic substrates despite their important roles in nematode neuromuscular and physiological processes.

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

“…This finding is in agreement with previous studies of C. elegans GAR-1, -2 and -3 and B. malayi GAR-2 and -3 that were also confirmed to be expressed throughout the entire life cycle ( Lee et al, 1999 , Lee et al, 2000 ; Gallo et al, 2023 ). In case of B. malayi the authors observed that GAR-3 mRNA is much highly abundant over the life cycle than in GAR-2, likely reflecting the acute physiological needs of the nematode ( Gallo et al, 2023 ). At this point it would be plausible to investigate if the GARs expression possesses the same feature across different nematode species.…”

“…C. elegans ’ GAR-3 regulates pharyngeal contractions ( Steger and Avery, 2004 ) and is also expressed in protractor muscles, as well as spicule-associated SPC and PCB cholinergic neurons ( Liu et al, 2007 ). GAR-3 in Brugia malayi has been found to be expressed in body wall muscle and neurons, as well as digestive and reproductive tissues, largely matching GAR-3 expression in C. elegans ( Gallo et al, 2023 ). Thus, it appears that GARs regulate many physiological functions of nematodes, some of which might be conserved across different taxa of this phylum.…”

“…Both earlier and more recent studies on nematode GARs have suggested that GAR-1 and GAR-2 are closely related in structure, and are both evolutionarily distinct from human M1-M5 receptors ( Lee et al, 1999 , Lee et al, 2000 ; Kimber et al, 2009 ). On the contrary, GAR-3's sequence was more similar to mammalian mAChRs ( Hwang et al, 1999 ; Gallo et al, 2023 ). Likewise, a study on D. melanogaster and Tribolium castaneum mAChR suggested two types of mAChRs (type A and B) in arthropods and most other invertebrate phyla including nematodes, where type A is structurally and pharmacologically similar to mammalian muscarinic receptors, whereas type B seems to be mainly found in invertebrates ( Collin et al, 2013 ; Ren et al, 2015 ).…”

“…Conversely, the divergence feature of type B mAChRs (including GAR-1 and GAR-2) indicates a common ancestor for the current mAChR family; indeed, an earlier study ( Ren et al, 2015 ) suggested that this is specific to protostomes. The significant evolutionary distance between nematode GAR-1/GAR-2 and mammalian muscarinic receptors reasonably leads to speculation on their different pharmacological profile, which has already been investigated in some nematodes ( Lee et al, 1999 , Lee et al, 2000 ; Kimber et al, 2009 ), thus positioning them as a suitable candidate for selective drug targeting ( Gallo et al, 2023 ).…”

“…The pharmacology of invertebrate mAChRs, namely GARs in nematodes, has been investigated by different research groups in various expression systems ( Hwang et al, 1999 ; Lee et al, 1999 , Lee et al, 2000 ; 2000 ; Suh et al, 2001 ; Kimber et al, 2009 ; Collin et al, 2013 ; Ren et al, 2015 ; Mateos-Hernández et al, 2020 ; Gallo et al, 2023 ). The take-home message of this research is that invertebrates possess two types of mAChRs: the single type A (an ortholog of GAR-3) is pharmacologically close to the mammalian type of receptor, while type B (orthologs of GAR-1 and GAR-2) had an atypical muscarinic profile ( Collin et al, 2013 ; Ren et al, 2015 ).…”