Degree Type

Dissertation

Date of Award

2008

Degree Name

Doctor of Philosophy

Department

Biomedical Sciences

First Advisor

Richard J. Martin

Second Advisor

Alan P. Robertson

Third Advisor

Jeffery Beetham

Abstract

Voltage-activated currents have been isolated in nematodes and are associated with depolarization (calcium channels) or recovery of the cell after the depolarization (potassium channels). Different subtypes of voltage-activated calcium channel have been identified in vertebrates. In nematodes, advances in C. elegans genomics led to the identification of voltage-activated calcium channel subtypes. These subtypes show homologies to vertebrate calcium channels but are pharmacologically and physiologically different. The understanding of the physiology of these different voltage-activated channels is becoming increasingly important as we try to lower the development of resistance to present anthelmintics. Major classes of anthelmintics produce their effect by modulating neuromuscular system either indirectly or directly. Therefore, it is important for us to understand the physiology of these channels in the worms to either identify novel drug target sites or understand the mechanism of development of resistance. Recently a new class of anthelmintic compounds, cyclo-octadepsipeptides, has been released for animal use. There modes of action include, latrophillin receptors activation, PF1 like neuropeptide release and more recently demonstrated activation of voltage-activated calcium dependent potassium channels. It is known from previous work done in A. suum and C. elegans that there are voltage-activated channels on the muscle membrane. Electrophysiological recordings in A. suum and other nematodes have shown that these currents may be modulated by different anthelmintics. We used voltage-clamp and current-clamp techniques to study voltage-activated currents in the pig parasitic nematode A. suum somatic muscle cells. We were able to isolate two types of voltage-activated calcium currents and one type of outward potassium current. We have characterized these channels pharmacologically and kinetically. We also realized that these channels, if modulated, could potentiate the response of cholinergic anthelmintics. Further, we used different endogenous nematode neuropeptides to modulate these currents.;Neuropeptides and their receptors offer novel drug target sites, not only for the development of new anthelmintics, but also to increase the potency of existing drugs. We anticipate that our observations will increase the understanding of worm physiology and validate the potential for exploring neuropeptide receptors for anthelmintic chemotherapy.

DOI

https://doi.org/10.31274/rtd-180813-17018

Publisher

Digital Repository @ Iowa State University, http://lib.dr.iastate.edu/

Copyright Owner

Saurabh Verma

Language

en

Proquest ID

AAI3316171

OCLC Number

299043342

ISBN

9780549687894

File Format

application/pdf

File Size

214 pages

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