INTERACTION OF LINDANE ISOMERS WITH CHLORIDE CURRENTS IN INSECT MEMBRANES - STERIC REQUIREMENTS FOR CHANNEL MODULATION AND BLOCK

Electrophysiological methods were used to characterize the modulatory effects of hexachlorocyclohexane isomers on GABA-activated chloride cu rrents in dissociated locust neurones. Conductance changes : associate d with hyperpolarising responses (or outward voltage-clamped currents) , evoked by brief GABA pulses, were inhibited by the gamma-isomer at 0 .01-1 mu M. The antagonistic action was noncompetitive and vol( age-in dependent: the concentration required for half-maximal block was <0.01 mu M. The rate of equilibration with the membrane/receptor was invers ely proportional to the concentration applied and was not dependent up on agonist-induced channel gating: effects were only partially reversi ble with extensive washing. In contrast the noninsecticidal beta-isome r was a low-affinity (greater than or equal to 10 mu M) positive modul ator of the inhibitory chloride channels. The modulatory action was vo ltage-dependent (more pronounced for inward currents at hyperpolarised potentials), did not reflect changes in chloride equilibrium potentia l, and was completely reversible. Nicotinic acetylcholine receptors we re consistently antagonised by the beta-isomer at 10 mu M. The above r esults were interpreted by computer-assisted modelling and are discuss ed in the context of a pharmacophore model for picrotoxinin and convul sant insecticides. The gamma-isomer overlays well with picrotoxinin an d a convulsant butyrolactone whereas the beta-isomer and anticonvulsan t butyrolactones conform to a different template. Liganding mechanisms and comparative/species differences in chloride channel pharmacology are discussed in the context of potential for development of invertebr ate-selective pesticides. (C) 1996 Academic Press, Inc.