Interactions of gephyrotoxin with the acetylcholine receptor-ionic channel complex. I. Blockade of the ionic channel.
The novel tricyclic 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. GyTX prolongs the falling phase of the muscle action potential and decreases delayed rectification, supporting the idea that the alkaloid blocks the voltage-sensitive potassium 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 degrees than at 22 degrees. 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 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 microM. Repetitive nerve stimulation led to a pronounced " rundown " in the EPCs which was frequency-dependent. These findings were taken as evidence that GyTX interacts with the acetylcholine receptor complex, causing a blockade of its channel mainly in the open conformation.
D000200:Action Potentials / Q000187:drug effects; D000470:Alkaloids / Q000494:pharmacology*; D000664:Amphibian Venoms / Q000494:pharmacology*; D000818:Animals; D005071:Evoked Potentials / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009132:Muscles / Q000502:physiology; D009469:Neuromuscular Junction / Q000502:physiology*; D011894:Rana pipiens; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000502:physiology*; D012584:Sciatic Nerve / Q000502:physiology*
D000470:Alkaloids; D000664:Amphibian Venoms; D007473:Ion Channels; D011950:Receptors, Cholinergic; C014569:gephyrotoxin