Mechanism of the calcium-dependent stimulation of transmitter release by 4-aminopyridine in synaptosomes.
The mechanism of the Ca2+-dependent stimulation of neurotransmitter release by 4-aminopyridine in synaptosomes was studied. The stimulation of gamma-[3H]aminobutyric acid and [3H]acetylcholine release by 4-aminopyridine was not significantly affected either by tetrodotoxin or by the absence of Na+ in the medium, whereas the toxin notably inhibited the release of both transmitters induced by veratridine. On the other hand, the release of labeled gamma-aminobutyric acid induced by 4-aminopyridine was inhibited by both La3+ and ruthenium red, two blockers of Ca2+ transport in synaptosomes. In other experiments, 4-aminopyridine had only a slight stimulatory effect, if any, on the influx of 45Ca2+ into synaptosomes, under both resting and K+-depolarizing conditions. Ruthenium red inhibited the stimulation by K+ of the 45Ca2+ uptake, and 4-aminopyridine did not antagonize this inhibition. We conclude that the transmitter-releasing action of 4-aminopyridine in synaptosomes does not involve an excitatory effect on the membrane which may result in the opening of voltage-sensitive Na+ channels. 4-Aminopyridine does not seem to act either by enhancing Ca2+ entry into the synaptosomes. It is proposed that 4-aminopyridine facilitates the coupling between Ca2+ binding and transmitter secretion at the presynaptic membrane.
Tapia
R
R
Sitges
M
M
Morales
E
E
D015761:4-Aminopyridine; D000109:Acetylcholine / Q000378:metabolism*; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000494:pharmacology*; D002794:Choline / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D018377:Neurotransmitter Agents / Q000378:metabolism*; D012964:Sodium / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000631:Aminopyridines; D018377:Neurotransmitter Agents; D014316:Tritium; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D012964:Sodium; D015761:4-Aminopyridine; D002794:Choline; D000109:Acetylcholine; D002118:Calcium