INTERACTIONS OF GEPHYROTOXIN WITH THE ACETYLCHOLINE RECEPTOR-IONIC CHANNEL COMPLEX .1. BLOCKADE OF THE IONIC CHANNEL

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  • 1 January 1984
    • journal article
    • research article
    • Vol. 25  (3) , 384-394
Abstract
The novel tricylic alkaloid, gephyrotoxin (GyTX), found in the skin secretions of the frog Dendrobates histrionicus, potentiates and blocks the indirectly elicited muscle twitch in a concentration-dependent manner in Rana pipiens. GyTX prolongs the falling phase of the muscle action potential and decreases delayed rectification, supporting the idea that the alkaloid blocks the voltage-sensitive K conductance of the electrically excitable membrane. The peak amplitude of the end-plate currents (EPC) and miniature end-plate currents (MEPC) were depressed, but no significant deviation from linearity relative to control was seen in the current-voltage relationship. The decay time constant of the EPC (.tau.EPC) was markedly shortened by GyTX, the effect being greater at 10.degree. than at 22.degree.. The relationship between the log of .tau.EPc and membrane potential disclosed a linear relationship at all concentrations tested, but a progressive loss of voltage sensitivity of .tau.EPC was seen when GyTX concentrations were increased. Also, the plot of 1/.tau.EPC against GyTX concentration revealed a linear relationship. The lack of voltage and time dependence suggests that GyTX has little effect on the ACh [acetylcholine] receptor-ionic channel complex in the closed conformation. Single-channel conductance studied by means of fluctuation analysis did not change after GyTX application, but the channel lifetime decreased by about 40% at clamp potentials of -105 mV and at a toxin concentration of 7.5 .mu.M. Repetitive nerve stimulation led to a pronounced rundown in the EPC which was frequency-dependent. GyTX interacts with the ACh receptor complex, causing a blockade of its channel mainly in the open conformation.