Nicotinic Receptors and Anthelmintic Resistance

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Nicotinic Receptors and Anthelmintic Resistance. Richard J. Martin, Adrian J. Wolstenholme, S. M. Williamson & Alan P. Robertson Department of Biomedical Sciences, Iowa State University, Ames, Iowa USA & Dept of Infectious Diseases, University of Georgia, Athens, Georgia. - PowerPoint PPT Presentation

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  • Nicotinic Receptors and Anthelmintic ResistanceRichard J. Martin, Adrian J. Wolstenholme, S. M. Williamson & Alan P. RobertsonDepartment of Biomedical Sciences, Iowa State University, Ames, Iowa USA & Dept of Infectious Diseases, University of Georgia, Athens, Georgia

  • Nicotinic AnthelminticsImidazothiazoles: levamisole, agonistTetrahydropyrimidines: pyrantel , agonistQuaternary Amines: bephenium , agonistAADs: monepantel , agonistMacfortines: paraherquamide & derquantel, antagonist

  • ABC

  • C. elegans nicotinic receptor subunitsJones et al., 2007: 29 subunits, 5 core structuresAADslevamisole

  • Muscle nAChRs in C. elegansC. elegans levamisole sensitive receptorG= 30 pS(Qian et al, 2008)C. elegans nicotine sensitive receptor

  • Pharmacological Diversity in Ascaris3 receptor types in Ascaris suum:

    N-type(low sensitivity to paraherquaminde)

    L-type(sensitive to paraherquamide and 2 desoxo-paraherquamide: derquantel)

    B-type(most sensitive to 2-desoxo-paraherquamide: derquantel)N-typeL-typeB-type

  • 3 channel currents & 3 nAChR subtypesABC

  • Asu-UNC38Asu-UNC29

  • Kopp et al. 2008 IJP: qtPCR A. caninum pyrantel-sensitive vs -resistant. Expression of aar-38, aar-63 and aar-29 reducedAlso no changes in E153 and Q57 pyrantel-specific sites Rayes et al. (2006)aar-29 -I50L, S206T,I309L (adults and larvae), I422L in both isolates and L466M in the NT isolate,aar-63-L393I(adults and larvae) No 38 amino-acid changes15-46 nucleotide changes

    Ref geneIsolateaar-38aar-63aar-29aar-19aar-15aar-8 PR/NT

    60SPR0.110.0130.290.660.00900.550.940.0460.620.540.0210.990.310.0180.890.410.0370.92NT0.370.022a1.20.070a1.50.035a0.550.00820.350.0910.450.018

  • nAChR subtypes and resistancelevamisole resistance

  • Monepantel resistance: Hco-mptl-1; Hco-des -2H; Hco-deg-3H; Rufener et al.,

  • Monepantel resistance: Hco-mptl-1, some lack splice acceptor (TTTCAG)

  • Molecular detection of resistance: levamisole & monepantelKopp et al., Did not find specific SNPs associated with resistance E153 & Q57 not associated with pyrantel resistanceExpression levels of UNC-38, UNC-29 and UNC-63 are reduced in pyrantel resistance Rufener et al., Hco-mptl-1 & Hco-des-2H, 1. a panel of mutations (null mutants) including deletions at intron-exon boundaries giving mis-spliced transients & premature stop codons2. Altered expression levels of Hco-mptl-1 & Hco-des-2H and & Hco-deg-3H

  • C. elegans proteins involved in levamisole resistance

  • Resistance may be due to a panel of functional null mutant genes with deletions and insertions and reduced expression of the target receptor genes + other sites!

  • AcknowledgmentsAlan RobertsonSally WilliamsonSreekanth PuttacharySam BuxtonCheryl ClarkAdrian WolstenholmeSteve KoppeAndrew KotzeSupported by NIH: R01 R 01 AI 047194