1205 Dr. Penfield Avenue
Montreal, Quebec H3A 1B1
My lab uses molecular genetic and electrophysiological approaches in the model nematode Caenorhabitis elegans to examine the role of ligand-gated ion channels in the sensitivity of worms to antiparasitic drugs. We have focused on the role of the glutamate-gated chloride channels (GluCls) in the sensitivity of nematodes to the widely used antiparasitic drug ivermectin. Our electrophysiological characterisation of two GluCl subunit proteins, GluCl-alpha-2 and GluCl-alpha-3, expressed in Xenopus oocytes showed that ivermectin acts directly on and activates chloride channels formed from these proteins. We also showed that mutations in genes encoding these two GluCl subunit proteins confer ivermectin resistance. Moreover, we discovered that several GluCls must be mutated simultaneously to confer high-level resistance, a result that has important implications for the evolution of drug resistance and the design of new antiparasitic drugs. More recently, as part of a collaborative research partnership with Crompton Inc., we are trying to identify promising targets for the development of new antiparasitic drugs. We have also been collaborating with Drs. Prichard and Beech to characterise ivermectin receptors from parasitic nematodes.
The evolution of pentameric ligand-gated ion channels. Adv Exp Med Biol. 2010;683:11-23. Review.
Beech RN, Wolstenholme AJ, Neveu C, Dent JA.
Nematode parasite genes: what's in a name? Trends Parasitol. 2010 Jul;26(7):334-40. Epub 2010 May 17.
Kehoe J, Buldakova S, Acher F, Dent J, Bregestovski P, Bradley J.
Aplysia cys-loop glutamate-gated chloride channels reveal convergent evolution of ligand specificity. J Mol Evol. 2009 Aug;69(2):125-41. Epub 2009 Jun 25.
Mounsey KE, Dent JA, Holt DC, McCarthy J, Currie BJ, Walton SF.
Molecular characterisation of a pH-gated chloride channel from Sarcoptes scabiei. Invert Neurosci. 2007 Sep;7(3):149-56. Epub 2007 Jun 30.