Resistance GABA receptors

Resistance to DDT has been developed in many insect species. Although there are some cases of metabolic resistance (e.g., strains high in DDT dehydrochlorinase activity), particular interest has been focused on kdr and super kdr mechanisms based upon aberrant forms of the sodium channel—the principal target for DDT. There are many examples of insects developing resistance to dieldrin. The best-known mechanism is the production of mutant forms of the target site (GABA receptor), which are insensitive to the insecticide. 

In one example (Lawrence and Casida 1984, Abalis et al. 1985) rat brain microsacs were used to test the action of cyclodiene insecticides such as dieldrin and endrin on the GABA receptors contained therein. The influx of radiolabeled CL into the microsacs via the pore channel of the receptor was inhibited by these chemicals. A similar assay was developed using microsacs from cockroach nerve. Assays with this preparation showed again the inhibitory effect of a cyclodiene (this time heptachlor epoxide) on CL influx. Also, that microsacs from cyclodiene resistant cockroaches were insensitive to the inhibitory effect of picrotoxinin, which binds to the same site on the GABA receptor (Kadous et al. 1983). 

Brooks, G.T. (1992). Progress in structure-activity smdies on cage convnlsants and related GABA receptor chloride ionophore antagonists. In D. Otto and B. Weber (Eds.) Insecticides Mechanism of Action and Resistance. Newcastle npon Tyne, UK Intercept Press, 237-242. 

Ffrench-Constant, T.A., Rochelau, J.C., and Steichen, J.C. et al. (1993). A point mutation in a Drosophila GABA receptor confers insecticide resistance. Nature, 363 49. 

Baclofen, labeled as a skeletal muscle relaxant binds to GABA receptors and depresses excitation. It is also useful in the treatment of paroxysms of trigeminal neuralgia. Baclofen is effective in patients with carbamazepine-resistant pain and has been used successfully to relieve attacks in patients previously unresponsive to carbamazepine or phenytoin. 

Jarolimek W, Misgeld U (1997) GABAB receptor-mediated inhibition of tetrodotoxin-resistant GABA release in rodent hippocampal CA1 pyramidal cells. J Neurosci 17 1025-32 Jeong SW, Ikeda SR (2000a) Effect of G protein heterotrimer composition on coupling of neurotransmitter receptors to N-type Ca(2+) channel modulation in sympathetic neurons. Proc Natl Acad Sci USA 97 907-12... 

Hosie AM, Ozoe Y, Koike K, Ohmoto T, Nikaido T, Sattelle DB (1996) Actions of Picrodendrin Antagonists on Dieldrin-sensitive and -resistant Drosophila GABA Receptors. Brit J Pharmacol 119 1569, and literature cited therein... 

GABA receptor, a target for several classes of insecticides, consists of two subunits, each with four transmembrane helices as determined from cloning and sequence analysis (641. Expression in Xenopus oocytes requires mRNA from only one of the subunits (651. Dieldrin resistant cockroaches were found to have reduced specific binding of picrotoxinin, which acts on the GABA receptor chloride ion channel (661. 

Cloning the Insect GABA Receptor and Resistance Mutations... 

The GABA receptor/chloride ionophore complex, which is located in the insect CNS and also in peripheral nerves, has been the focus of intense interest as both a target of insecticidal action and in its role in resistance [85]. 

Antagonism of the GABA Receptor of Dieldrin-Resistant Houseflies by Fipronil and Its Analogues... 

HJEBOB binding to the head membranes of the dieldrin-resistant (OCR) strain of houseflies was investigated. The OCR houseflies had an alanine-to-serine mutation at the 299-position of the RDL subunit. Scatchard analysis showed that EBOB bound to the head membranes of the OCR houseflies with 4-fold lower affinity than to those of the susceptible (WHO/SRS) strain. The membranes of the OCR strain were found to have 45-fold lower affinity for dieldrin than those of the WHO/SRS strain. By contrast, the membranes of the OCR strain showed only 2-fold lower affinity for fipronil than those of the WHO/SRS strain. The alanine-to-serine mutation does not hinder the binding of fipronil to the housefly GABA receptor. 

Note NaCh = sodium channel RF = resistance factor, which is LDjq resistant strain/LDjQ susceptible strain GABA = gamma amino butyric acid receptor PBO = piperonyl butoxide. 

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