Pharmacological induction of rhythmical activity and plateau action potentials in unmyelinated axons.
The physiological function of the axon is to conduct short all-or-none action potentials from their site of initiation (usually the cell body) to the synapse. To ensure this function, both passive and active biophysical properties of the axons are tuned very precisely, especially the voltage-dependent ionic conductances to sodium and potassium. Under normal conditions, axons are not spontaneously active. Minor modifications of their ionic micro-environment or slight changes in the membrane properties are however sufficient to induce rhythmical activity and modify the time course of the action potentials. These modifications can be induced by a variety of pharmacological agents. Some typical examples taken from original studies on invertebrate preparations are illustrated. The experiments were carried out on two axonal preparations: the giant axon of the squid Loligo forbesi and the giant axon of the cockroach Periplaneta americana. The axons were 'space-clamped' and studied under both current-clamp and voltage-clamp conditions. Voltage-clamp experiments were used to dissect out the mechanisms underlying repetitive activity and to extract the relevant parameters. These parameters were then used to rebuild the observed effects using an extended version of the Hodgkin and Huxley (1952, J Physiol (Lond) 117, 500-544) formulation. One easy way to get repetitive firing in both preparations is to reduce potassium conductance. The effect of 4-aminopyridine on squid axon is illustrated here. The experimental results, including the occurrence of bursts of activity, can be described by adding a time- and voltage-dependent block of the potassium channels to the original Hodgkin and Huxley (1952, J Physiol (Lond) 117, 500-544) model. Repetitive spike activity and plateau action potentials are also produced when the depolarising effect of the voltage-dependent potassium current is counterbalanced by a maintained inward sodium current. This maintained sodium current can be due to several different mechanisms. This will be illustrated by five structurally unrelated molecules: two scorpion toxins, two insecticide molecules and one sea anemone toxin. One toxin purified from the venom of the scorpion Buthotus judaicus (insect toxin 1) exerts its effects by shifting the sodium activation curve towards more hyperpolarized potentials. Another toxin purified from the venom of another scorpion Androctonus australis (mammal toxin 1) modifies a significant proportion of normal (fast) sodium channels into slowly activating and inactivating sodium channels. The main effect of the insecticide DDT is to maintain sodium channels in the 'open' configuration. Another insecticide molecule known to induce repetitive activity, S-bioallethrin, activates voltage-dependent sodium channels with slow activation and inactivation kinetics. The sea anemone toxin anthopleurin A, purified from the venom of Anthopleura xanthogrammica, delays inactivation of the sodium current without changing its activation kinetics. These examples show that minor modifications of the properties of the nerve membrane are sufficient to alter nerve function. These deleterious effects will be amplified at the synapse through dramatic changes in transmitter release and will lead eventually to disastrous alterations of brain function.
Pichon
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Equipe de Neurobiologie, Neuropharmacologie Moleculaire et Ecotoxicologie, CNRS, Universite de Rennes, France.
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001369:Axons / Q000187:drug effects*; D049832:Decapodiformes; D004553:Electric Conductivity; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D009186:Myelin Sheath / Q000502:physiology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D010526:Periplaneta; D015221:Potassium Channels / Q000502:physiology; D012604:Scorpion Venoms / Q000494:pharmacology; D012615:Sea Anemones; D015222:Sodium Channels / Q000502:physiology
D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D015221:Potassium Channels; D012604:Scorpion Venoms; D015222:Sodium Channels; C012746:anthopleurin-A; D015761:4-Aminopyridine