Investigating the molecular basis of resistance and pyrethroid selectivity at acarine sodium channels

Blockley, Alix Dawn (2017) Investigating the molecular basis of resistance and pyrethroid selectivity at acarine sodium channels. Doctoral thesis, Birkbeck, University of London.

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Abstract

Many acarine (tick and mite) species are ectoparasites of humans, livestock and domestic pets, where they spread disease and impact adversely on health. They are normally controlled through the application of acaricides; however, the prolonged use of individual compounds has resulted in many species developing resistance to specific pesticides. This thesis describes investigations into the molecular properties that determine the resistance to and selectivity of pyrethroids, an important class of pesticides that act on the voltage-gated sodium channels (VGSCs) of arthropod neurons. Comparison of insect and acarine VGSC sequences, coupled with molecular modelling studies, have identified a residue at amino-acid position 933 (M. domestica numbering) found within a putative pyrethroid binding pocket that may contribute to a greater selectivity of pyrethroids with comparatively larger halogenated groups for acarine VGSCs compared to those of insects. This is due to the presence of a smaller glycine residue at position 933 in acarine channels, compared to a cysteine residue in insect channels, which may enhance the binding of such pyrethroids (O'Reilly et al., 2014). This model is supported by the findings of Jonsson et al 2010, that R. microplus cattle ticks carrying the amino acid substitution G933V, are resistant to the pyrethroid flumethrin, which has a comparatively larger halogenated group, but not the pyrethroid cypermethrin, which has a comparatively smaller halogenated group. Work in this thesis describes progress made in the investigation of such specificity; involving sequencing studies, two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes involving insect and acarine VGSCs, and whole arthropod bioassays. While this work cannot conclusively disprove the model proposed by O’Reilly et al 2014, it suggests that the mechanisms of selectivity for pyrethroids in arthropods may involve the interplay of several factors, rather than being solely based upon structural variations in their VGSCs.

Item Type: Thesis (Doctoral)
Copyright Holders: The copyright of this thesis rests with the author, who asserts his/her right to be known as such according to the Copyright Designs and Patents Act 1988. No dealing with the thesis contrary to the copyright or moral rights of the author is permitted.
School/Department: School of Science > Biological Sciences
Depositing User: ORBIT Editor
Date Deposited: 13 Jun 2017 16:48
Last Modified: 13 Jun 2017 16:48
URI: http://bbktheses.da.ulcc.ac.uk/id/eprint/252

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