A new family of glutamate-gated chloride channels in parasitic sea louse Caligus rogercresseyi: A subunit refractory to activation by ivermectin is dominant in heteromeric assemblies.

Autor: Tribiños F; Centro de Estudios Científicos (CECs), Valdivia, Chile., Cuevas P; Centro de Estudios Científicos (CECs), Valdivia, Chile., Cornejo I; Centro de Estudios Científicos (CECs), Valdivia, Chile.; Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebastián, Valdivia, Chile., Sepúlveda FV; Centro de Estudios Científicos (CECs), Valdivia, Chile.; Facultad de Medicina y Ciencia, Universidad San Sebastián, Valdivia, Chile., Cid LP; Centro de Estudios Científicos (CECs), Valdivia, Chile.; Facultad de Medicina y Ciencia, Universidad San Sebastián, Valdivia, Chile.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2023 Mar 14; Vol. 19 (3), pp. e1011188. Date of Electronic Publication: 2023 Mar 14 (Print Publication: 2023).
DOI: 10.1371/journal.ppat.1011188
Abstrakt: Sea louse ectoparasitosis is a major threat to fish aquaculture. Avermectins such as ivermectin and emamectin have been effectively used against sea louse infestation, but the emergence of resistance has limited their use. A better understanding of the molecular targets of avermectins is essential to the development of novel treatment strategies or new, more effective drugs. Avermectins are known to act by inhibiting neurotransmission through allosteric activation of glutamate-gated chloride channels (GluCls). We have investigated the GluCl subunit present in Caligus rogercresseyi, a sea louse affecting aquaculture in the Southern hemisphere. We identify four new subunits, CrGluCl-B to CrGluCl-E, and characterise them functionally. CrGluCl-A (previously reported as CrGluClα), CrGluCl-B and CrGluCl-C all function as glutamate channel receptors with different sensitivities to the agonist, but in contrast to subunit -A and -C, CrGluCl-B is not activated by ivermectin but is rather antagonised by the drug. CrGluCl-D channel appears active in the absence of any stimulation by glutamate or ivermectin and CrGluCl-E does not exhibit any activity. Notably, the expression of CrGluCl-B with either -A or -C subunits gives rise to receptors unresponsive to ivermectin and showing altered response to glutamate, suggesting that coexpression has led to the preferential formation of heteromers to which the presence of CrGluCl-B confers the property of ivermectin-activation refractoriness. Furthermore, there was evidence for heteromer formation with novel properties only when coexpressing pairs E/C and D/B CrGluCl subtypes. Site-directed mutagenesis shows that three transmembrane domain residues contribute to the lack of activation by ivermectin, most crucially Gln 15' in M2, with mutation Q15'T (the residue present in ivermectin-activated subunits A and C) conferring ivermectin activation to CrGluCl-B. The differential response to avermectin of these Caligus rogercresseyi GluClsubunits, which are highly conserved in the Northern hemisphere sea louse Lepeophtheirus salmonis, could have an influence on the response of these parasites to treatment with macrocyclic lactones. They could serve as molecular markers to assess susceptibility to existing treatments and might be useful molecular targets in the search for novel antiparasitic drugs.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Tribiños et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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