Skip to main content
SpringerLink
Log in

Blockage of chloride channels and anion transporters with pesticidal natural products and their synthetic analogs

  • Published:
Phytochemistry Reviews Aims and scope Submit manuscript

Abstract

Ligand-gated chloride channels mediate a variety of functions in excitable membranes of nerve and muscle in insects, and have a long history as targets for neurotoxic insecticides. Recent findings from our laboratory confirm that the natural product silphinenes and their semi-synthetic analogs share a mode of action with the established ligand-gated chloride channel antagonist, picrotoxinin. The silphinenes are non-selective, being roughly equipotent on insect and mammalian receptors, but also possess lethal and neurotoxic effects on a dieldrin-resistant strain of Drosophila melanogaster. These findings suggest that silphinenes act on insect GABA receptors in a way that is different from picrotoxinin, and it is possible that resistant insect populations in the field could be controlled with insecticidal compounds derived from the silphinenes. Voltage-gated chloride channels and anion transporters provide additional classes of validated targets for insecticidal/nematicidal action. Anion transporter blockers are toxic to insects via an action on the gut, and RNAi studies implicate voltage-gated chloride channels in nematode muscle as another possible target. There was no cross resistance to DIDS in a dieldrin-resistant strain of Drosophila melanogaster, and no evidence for neurotoxicity. The potent paralytic actions of anion transporter blockers against nematodes, and stomach poisoning activity against lepidopteran larvae suggests they are worthy of further investigation as commercial insecticidal/nematicidal agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ATs:

Anion transporters

9-AC:

Anthracene-9-carboxylic acid

CNS:

Central nervous system

CBEs:

Chloride-bicarbonate exchangers

DIDS:

4,4′-diisothiocyanatostilbene 2,2′-disulfonic acid

DST:

3,5-dihydroxy-4-isopropyl stilbene

GluRCl:

Glutamate-gated chloride channels

IAA-94:

Indanyloxy acetic acid

LGCCs:

Ligand-gated chloride channels

NPPB:

5-nitro-2-(3-phenylpropylamino) benzoic acid

rdl:

Resistance to dieldrin

VGCCs:

Voltage-gated chloride channels

References

  • Asmild M, Willumsen N (2000) Chloride channels in the plasma membrane of a foetal Drosophila cell line, S2. Pflug Arch Eur J Physiol 439:759–764

    Article  CAS  Google Scholar 

  • Bloomquist JR (1994) Cyclodiene resistance at the insect GABA receptor/chloride channel complex confers broad cross resistance to convulsants and experimental phenylpyrazole insecticides. Arch Insect Biochem Physiol 26(1):69–79

    Article  PubMed  CAS  Google Scholar 

  • Bloomquist JR (2001) GABA and glutamate receptors as biochemical sites for insecticide action. In: Ishaaya I (ed) Biochemical sites of insecticide action and resistance. Springer, Berlin, pp 17–41

    Google Scholar 

  • Bloomquist JR (2003) Chloride channels as tools for developing selective insecticides. Arch Insect Biochem Physiol 54:145–156

    Article  PubMed  CAS  Google Scholar 

  • Bloomquist JR, Boina D, Chow E, Carlier PR, Reina M, Gonzalez-Coloma A (2008) Mode of action of the plant-derived silphinenes on insect and mammalian GABAA receptor/chloride channel complex. Pestic Biochem Physiol 91:17–23

    Article  CAS  Google Scholar 

  • Boina D, Bloomquist JR (2009) Toxicity and disruption of midgut physiology in larvae of the European corn borer, Ostrinia nubilalis, by anion transporter blockers. Arch Insect Biochem Physiol 70:151–161

    Article  PubMed  CAS  Google Scholar 

  • Boina D, Bloomquist JR (2010) Reduced expression of voltage-gated chloride channel genes in Caenorhabditis elegans: Implications for the mode of action of chloride channel-directed nematicides. Pestic Biochem Physiol (in press)

  • Boina D, Lewis EE, Bloomquist JR (2008) Nematicidal activity of anion transport blockers against Meloidogyne incognita, Caenorhabditis elegans, and Heterorhabditis bacteriophora. Pest Manag Sci 64:646–653

    Article  PubMed  CAS  Google Scholar 

  • Boudko DY, Moroz LL, Harvey WR, Linser PJ (2001) Alkalinization by chloride/bicarbonate pathway in larval mosquito midgut. Proc Natl Acad Sci USA 98:15354–15359

    Article  PubMed  CAS  Google Scholar 

  • Cabantchik ZI, Greger R (1992) Chemical probes for anion transporters of mammalian cell membranes. Am J Physiol 262:C803–C827

    PubMed  CAS  Google Scholar 

  • Casida JE (2009) Pest toxicology: the primary mechanisms of pesticide action. Chem Res Toxicol 22:609–619

    Article  PubMed  CAS  Google Scholar 

  • Chao AC, Koch AR, Moffett DF (1989) Active chloride transport in isolated posterior midgut of tobacco hornworm (Manduca sexta). Am J Physiol 257:R752–R761

    PubMed  CAS  Google Scholar 

  • Ciche TA, Ensign JA (2003) For the insect pathogen Photorhabdus luminiscens, which end of a nematode is out? Appl Environ Microbiol 69:1890–1897

    Article  PubMed  CAS  Google Scholar 

  • Cleland TA, Selverston AI (1995) Glutamate-gated inhibitory currents of central pattern generator neurons in the lobster stomatogastric ganglion. J Neurosci 15(10):6631–6639

    PubMed  CAS  Google Scholar 

  • Cully DF, Paress PF, Liu KK, Schaeffer JM, Arena JP (1996) Identification of a Drosophila melanogaster glutamate-gated chloride channel sensitive to the antiparasitic agent avermectin. J Biol Chem 271:20187–20191

    Article  PubMed  CAS  Google Scholar 

  • El Hassani AK, Giurfa M, Gauthier M, Armengaud C (2008) Inhibitory neurotransmission and olfactory memory in honeybees. Neurobiol Learn Mem 90:585–590

    Google Scholar 

  • Fahlke C (2001) Ion permeation and selectivity in ClC-type chloride channels. Am J Physiol Renal Physiol 280:F748–F757

    PubMed  CAS  Google Scholar 

  • Ferroni S, Marchini C, Nobile M, Rapisarda C (1997) Characterization of an inwardly rectifying chloride conductance expressed by cultured rat cortical astrocytes. Glia 21:217–227

    Article  PubMed  CAS  Google Scholar 

  • ffrench-Constant R, Steichen J, Rocheleau T, Aronstein K, Roush R (1993) A single-amino acid substitution in a γ-aminobutyric acid subtype A receptor locus is associated with cyclodiene insecticide resistance in Drosophila populations. Proc Natl Acad Sci USA 90:1957–1961

    Article  PubMed  CAS  Google Scholar 

  • Forst S, Dowds B, Boemare N, Stackebrandt E (1997) Xenorhabdus and Photorhabdus spp.: bugs that kill bugs. Annu Rev Microbiol 51:47–72

    Article  PubMed  CAS  Google Scholar 

  • Gengs C, Leung H-T, Skingsley D, Iovchev M, Yin Z, Semenev E, Burg M, Hardie R, Pak W (2002) The target of Drosophila photoreceptor synaptic transmission is a histamine-gated chloride channel encoded by ort (hclA). J Biol Chem 277:42113–42120

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Coloma A, Reina M, Cabrera R, Castanera P, Gutierrez C (1995) Antifeedant and toxic effects of sesquiterpenes from Senecio palmensis to Colorado potato beetle. J Chem Ecol 21:1255–1270

    Article  CAS  Google Scholar 

  • Gonzalez-Coloma A, Gutierrez C, Cabrera R, Reina M (1997) Silphinene derivatives: their effects and mode of action on Colorado potato beetle. J Agric Food Chem 45:946–950

    Article  CAS  Google Scholar 

  • Gonzalez-Coloma A, Valencia F, Martin N, Hoffmann JJ, Hutter L, Marco JA, Reina M (2002) Silphinene sesquiterpenes as model insect antifeedants. J Chem Ecol 28:117–129

    Article  PubMed  CAS  Google Scholar 

  • Hu K, Webster JM (2000) Antibiotic production in relation to bacterial growth and nematode development in Photorhabdus-Heterorhabditis infected Galleria mellonella larvae. FEMS Microbiol Lett 189:219–223

    PubMed  CAS  Google Scholar 

  • Hu K, Li J, Webster JM (1999) Nematicidal metabolites produced by Photorhabdus luminescens (Enterobacteriaceae), bacterial symbiont of entomopathogenic nematodes. Nematology 1:457–469

    Article  CAS  Google Scholar 

  • Jentsch TJ, Stein V, Weinreich F, Zdebik AA (2002) Molecular structure and physiological function of chloride channels. Physiol Rev 82:503–568

    PubMed  CAS  Google Scholar 

  • Ludmerer SW, Warren VA, Williams BS, Zheng Y, Hunt DC, Ayer MB, Wallace MA, Chaudhary AG, Egan MA, Meinke PT, Dean DC, Garcia ML, Cully DF, Smith MM (2002) Ivermectin and nodulisporic acid receptors in Drosophila melanogaster contain both gamma-aminobutyric acid-gated Rdl and glutamate-gated GluCl alpha chloride channel subunits. Biochemistry 41:6548–6560

    Article  PubMed  CAS  Google Scholar 

  • Lummis S (1990) GABA receptors in insects. Comp Biochem Physiol 95C:1–8

    CAS  Google Scholar 

  • Machaca K, Defelice LJ, Hernault SWL (1996) A novel chloride channel localizes to Caenorhabditis elegans spermatids and chloride channel blockers induce spermatid differentiation. Dev Biol 176:1–16

    Article  PubMed  CAS  Google Scholar 

  • Malekova L, Tomaskova J, Novakova M, Stefanik P, Kopacek J, Lokatos B, Pastorekova S, Krizanova O, Breier A, Ondrias K (2007) Inhibitory effect of DIDS, NPPB, and phloretin on intracellular chloride channels. Pflugers Arch Eur J Physiol 455:349–357

    Article  CAS  Google Scholar 

  • Mullin CA, Chyb S, Eichenseer H, Hollister B, Frazier JL (1994) Neuroreceptor mechanisms in insect gestation: a pharmacological approach. J Insect Physiol 40:913–931

    Article  CAS  Google Scholar 

  • Mullin CA, Gonzalez-Coloma A, Gutierrez C, Reina M, Eichenseer H, Hollister B, Chyb S (1997) Antifeedant effects of some novel terpenoids on chrysomelidae beetles: comparisons with alkaloids on an alkaloid-adapted and nonadapted species. J Chem Ecol 23:1851–1866

    Article  CAS  Google Scholar 

  • Nagel W, Somieski P, Katz U (2001) Selective inhibition of Cl− conductance in toad skin by blockers of Cl− channels and transporters. Am J Physiol Cell Physiol 281:C1223–C1232

    PubMed  CAS  Google Scholar 

  • Pedersen TH, Paoli FD, Nielsen OB (2005) Increased excitability of acidified skeletal muscle: role of chloride conductance. J Gen Physiol 125:237–246

    Article  PubMed  CAS  Google Scholar 

  • Pusch M, Accardi A, Liantonio A, Guida P, Traverso S, Camerino DC, Conti F (2002) Mechanisms of block of muscle type CLC chloride channels (Review). Mol Mem Biol 19:285–292

    Article  CAS  Google Scholar 

  • Raymond V, Sattelle DB (2002) Novel animal-health drug targets from ligand-gated chloride channels. Nat Rev 1:427–436

    Article  CAS  Google Scholar 

  • Raymond V, Sattelle DB, Lapied B (2000) Co-existence in DUM neurons of two GluCl channels that differ in their picrotoxin sensitivity. NeuroReport 11:2695–2701

    Article  PubMed  CAS  Google Scholar 

  • Reina M, Nold M, Santana O, Orihuela JC, Gonzalez-Coloma A (2002) C-5-Substituted antifeedant silphinene sesquiterpenes from Senecio palmensis. J Nat Prod 65:448–453

    Article  PubMed  CAS  Google Scholar 

  • Rohrer S, Arena J (1995) Structural and functional characterization of insect genes encoding ligand-gated chloride channel subunits. In: Clark JM (ed) Molecular action of insecticides on ion channels Amer Chem Soc Symp Ser 591, Washington, DC, pp 264–283

  • Shanbhag S, Tripathi S (2005) Electrogenic H+ transport and pH gradients generated by a V-H+-ATPase in the isolated perfused larval Drosophila midgut. J Membr Biol 206:61–72

    Article  PubMed  CAS  Google Scholar 

  • Sterling D, Casey JR (2002) Bicarbonate transport proteins. Biochem Cell Biol 80:483–497

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Telfer WH (1998) Cyclic-AMP-induced water uptake in a moth ovary: inhibition by bafilomycin and anthracene-9-carboxylic acid. J Exp Biol 201:1627–1635

    PubMed  CAS  Google Scholar 

  • Yamamoto D, Suzuki N (1987) Single-channel recordings of chloride currents in primary cultured Drosophila neurons. Arch Insect Biochem Physiol 6:151–158

    Article  Google Scholar 

  • Zhao X, Yeh JG, Salgado VL, Narahashi T (2004) Fipronil is a potent open channel blocker of glutamate-activated chloride channels in cockroach neurons. J Pharmacol Exp Ther 310:192–201

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Dhana Raj Boina was partially supported by a David and Lillian Francis memorial fellowship from Virginia Tech for dissertation research. We thank Dr. Werner Geldenhuys, NEOUCOP, for providing the molecular overlay of DST/DIDS.

Author information

Authors and Affiliations

  1. Department of Entomology and Nematology, Citrus Research and Education Center, University of Florida, Lake Alfred, FL, 33850, USA

    Dhana Raj Boina

  2. Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, 2055 Mowry Road, PO Box 100009, Gainesville, FL, 32610-00009, USA

    Jeffrey R. Bloomquist

Authors
  1. Dhana Raj Boina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey R. Bloomquist
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey R. Bloomquist.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boina, D.R., Bloomquist, J.R. Blockage of chloride channels and anion transporters with pesticidal natural products and their synthetic analogs. Phytochem Rev 10, 217–226 (2011). https://doi.org/10.1007/s11101-010-9179-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11101-010-9179-8

Keywords

Search

Navigation