Picrotoxinin receptor

Ozoe Y, Matsumura F. 1986. Structural requirements for bridged bicyclic compounds acting on picrotoxinin receptor. J Agric Food Chem 34 126-134. 

Kadous, A.A, Ghiasuddin, S.M., and Matsumura, E. (1983). Differences in the picrotoxinin receptor between cyclodiene-resistant and susceptible strains of the German cockroach. Pesticide Biochemistry and Physiology 19, 157. 

Matsumura F. 1985. Involvement of picrotoxinin receptor in the action of cyclodiene insecticides. Neurotoxicology 6(2) 139-164. 

Tanaka K, Matsumura F. Altered picrotoxinin receptor as a cause for cyclodiene resistance in Musca domestica, Aedes aegypti and Blattella germanica. In Clark JM, ed. Membrane Receptor Enzyme Targets Insecicide Action, New York, NY, USA, 1986. New York, NY Plenum, 33-49. 

Cyclodiene insecticides produce intense nerve excitation in both vertebrate and invertebrate species (Matsumura 1985 Matsumura and Tanaka 1984). It has been suggested that the biochemical mechanisms by which these chemicals induce hyperexcitation in the central nervous system are due to the release of neurotransmitters caused by the interactions of the insecticide with the picrotoxinin receptor. 

Dieldrin (1), y-BHC (2) and picrotoxinin (3,A) have been shown to influence the presynaptic events on the American cockroach (Periplaneta americana) central nervous system (CNS) and thereby to stimulate excitatory neurotransmitter release. As to the cause for such stimulation, we have proposed that these agents specifically interact with the putative picrotoxinin receptor closely associated with the chloride ionophore in the y-aminobutyric acid-chloride iono-phore complex (designated as the GABA receptor system in this paper) at the presynaptic region, and that such interaction causes inhibition of chloride ion uptake. This uptake is regulated by GABA to modulate the presynaptic membrane potential (4-8). 

Both mammalian and insect picrotoxinin receptors have recently been reported to respond to a variety of cyclodiene-type insecticides By... 

In view of the recent discovery of the similarities of action between picrotoxinin and cyclodiene-type insecticides as described above (3,8), it appears worthwhile to reexamine the structural requirement of picrotoxinin-type convulsants for interaction with the specific picrotoxinin binding site. Another objective of this study is to obtain supporting evidence for the role of the picrotoxinin receptor in the mode of action of cyclodiene-type insecticides by synthesizing compounds that structurally bridge the gap between cyclodiene compounds and picrotoxinin. 

Figure 4. Electronegative and steric bulkiness sites of compounds acting on picrotoxinin receptors. Reproduced from Ref. (57) (Copyright, 1986 Amer. Chem. Society).

Compared with the accumulated biochemical knowledge on GABA, benzodiazepine, and picrotoxinin receptors, and the Cl channel complex in mammalian brains (see Ref. 41), the available information on insects and nematodes is quite limited. 

Difficulties in measuring ligand binding to GABA receptors in insects (42) could be one of the reasons for such a scarcity of information. The only results available are a few studies on picrotoxinin receptors and Cl channels in the central nervous systems and muscles of the American and German cockroaches (4,5,7), and on putative benzodiazepine receptors in housefly thoracic muscles (42). According to these reports there are several differences in drug specificities between the receptors of mammals and insects (4,42). 

In the current study, we have made an attempt to characterize the mechanism of action of avermectin Bla in the cockroach muscle and central nervous system. We report finding that avermectin opens the Cl channel apparently independent of actions on GABA, benzodiazepine, and picrotoxinin receptors. The methods used for this part of the study have been published elsewhere (44) ... 

The picrotoxinin receptor, though it is an integral part of the GABA complex, is known to be a receptor independent from the GABA and benzodiazepine receptors in mammalian brains (52). 

Using the pHjdihydropicrotoxinin binding test (52), the effect of avermectin on the picrotoxinin receptor was examine . No significant effect of avermectin on pH]dihydropicrotoxinin binding to the membranes of the brain and the muscle of the American cockroach was found. At higher concentrations of avermectin (10 5 m) a slight inhibition was observed. 

Recent studies from our research group have demonstrated the presence of GABA and picrotoxinin receptors and the Cl channel complex in the central nervous system of American and German cockroaches (4,7) In the current study, avermectin was found to increase chloride uptake in the leg muscle cells of the American cockroach Avermectin may act as a presynaptic inhibitor by opening Cl channels of the GABA synapse so that the presynaptic membrane is not able to release an excitatory transmitter, or as a postsynaptic inhibitor by opening the chloride channel in the postsynaptic region ... 

The elimination of y-BHC symptoms by avermectin may be explained as follows The primary action site of y-BHC is likely to involve the picrotoxinin receptor (5). Therefore, one could assume that y-BHC, at least in part, acts in an identical manner to picrotoxinin which has already been shown to antagonize the action of avermectin Kass et al. (29) reported two types of avermectin action on the nervous system of the nematode, based on the inhibition by picrotoxinin. One is the avermectin-induced blockage of interneuron-excitatory motorneuron transmission, which can be reversed by picrotoxinin. The other is the avermectin-induced blockage of the transmission between inhibitory motoneurons and muscle, which cannot be reversed by picrotoxinin. 

In summary, avermectin has been found to interact directly with the chloride channel in the muscle and the central nervous system of the American cockroach. This action of avermectin appears to occur independently from GABA, benzodiazepine, and picrotoxinin receptors in this species ... 

It has been clearly shown that cyclodiene-type insecticides act on the TBPS site (15,16,25) and the cockroach picrotoxinin receptor (22,24) which is presumed to be the site of action for BPEs, but neither dieldrin nor yBHC at 10 yM affected Pr-BP binding Other GABA receptor-related and Cl" channel-related compounds described below, some of which have been reported as TBPS binding modulators (4,26-31), were inactive in inhibiting [%]Pr-BP binding to the housefly head membranes deltamethrin (10 yM), allethrin (10 yM), suriclone (0 1 yM), avermectin B (1 yM), clonazepam (10 yM), etomidate chloride (10 yM), pitrazepin (5 yM), phenobarbital sodium (10 yM), Ro 5-4864 (10 yM), Ro 15-1788 (5 yM), RU 5135 (0.5 yM), and DIDS (10 yM). 

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