Presynaptic Mechanism of Action of 4‐Aminopyridine: Changes in Intracellular Free Ca2+ Concentration and Its Relationship to B‐50 (GAP‐43) Phosphorylation

doi:10.1111/j.1471-4159.1991.tb03437.x

Paper

Presynaptic Mechanism of Action of 4‐Aminopyridine: Changes in Intracellular Free Ca2+ Concentration and Its Relationship to B‐50 (GAP‐43) Phosphorylation

Published Jun 1, 1991 · F. Heemskerk, L. Schrama, W. Ghijsen

Journal of Neurochemistry

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32

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2

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Abstract

Abstract: Recently we have shown that 4‐aminopyridine (4‐AP), a drug known to enhance transmitter release, stimulates the phosphorylation of the protein kinase C substrate B‐50 (GAP‐43) in rat brain synaptosomes and that this effect is dependent on the presence of extracellular Ca2+. Hence, we were interested in the relationship between changes induced by 4‐AP in the intracellular free Ca2+ concentration ([Ca2+]i) and B‐50 phosphorylation in synaptosomes. 4‐AP (100 μM) elevates the [Ca2+]i (as determined with fura‐2) to approximately the same extent as depolarization with 30 mM K+ (from an initial resting level of 240 nM to ∼480 nM after treatment). However, the underlying mechanisms appear to be different: In the presence of 4‐AP, depolarization with K+ still evoked an increase in [Ca2+]i, which was additive to the elevation caused by 4‐AP. Several Ca2+ channel antagonists (CdCl2, LaCl3, and diphenylhydantoin) inhibited the increase in B‐50 phosphorylation by 4‐AP. It is interesting that the increase in [Ca2+]i and the increase in B‐50 phosphorylation by 4‐AP were attenuated by tetrodotoxin, a finding pointing to a possible involvement of Na+ channels in this action. These results suggest that 4‐AP (indirectly) stimulates both Ca2+ influx and B‐50 phosphorylation through voltage‐dependent channels by a mechanism dependent on Na+ channel activity.

In Vitro Study

Study Snapshot

4aminopyridine indirectly stimulates both intracellular free Ca2+ concentration and B50 phosphorylation in synaptosomes through voltage-dependent channels, with Na+ channel activity playing a role.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Presynaptic Mechanism of Action of 4‐Aminopyridine: Changes in Intracellular Free Ca2+ Concentration and Its Relationship to B‐50 (GAP‐43) Phosphorylation

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References

Evidence for the Binding of Calmodulin to Endogenous B‐50 (GAP‐43) in Native Synaptosomal Plasma Membranes

Calmodulin binding to endogenous B-50 in synaptosomal plasma membranes is of physiological relevance, potentially regulating neurite outgrowth and neurotransmitter release.

Depolarization‐Induced Phosphorylation of the Protein Kinase C Substrate B‐50 (GAP‐43) in Rat Cortical Synaptosomes

Depolarization-induced phosphorylation of protein kinase C substrate B-50 in rat cortical synaptosomes is dependent on extracellular calcium levels, suggesting potential relevance for depolarization-induced transmitter release.

Evidence for a relationship between B-50 (GAP-43) and [3H]noradrenaline release in rat brain synaptosomes.

B-50 (GAP-43) and noradrenaline release in rat brain synaptosomes are linked, with both PKC and calmodulin-dependent processes playing a role in the release event.

4‐Aminopyridine Stimulates B‐50 (GAP43) Phosphorylation and [3H]Noradrenaline Release in Rat Hippocampal Slices

4aminopyridine stimulates B50 phosphorylation and neurotransmitter release in rat hippocampal slices, providing insight into the molecular mechanisms of epileptogenesis.

Calcium/calmodulin-dependent protein kinase II increases glutamate and noradrenaline release from synaptosomes

Activating calcium/calmodulin-dependent protein kinase II in nerve terminals increases the release of neurotransmitters glutamate and noradrenaline, supporting the hypothesis that activation in nerve terminals removes constraints on neurotransmitter release.

Citations

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Levetiracetam, valproic acid, and topiramate do not inhibit the rise in calcium induced by 4-AP in hippocampal nerve endings, suggesting their mechanisms of action are unrelated to a decrease in presynaptic Na+ or Ca2+ channels.

Vinpocetine inhibits glutamate release induced by the convulsive agent 4-aminopyridine more potently than several antiepileptic drugs

Vinpocetine effectively inhibits glutamate release induced by 4-aminopyridine more potently than several common antiepileptic drugs, potentially contributing to its anticonvulsant effects.

Antiepileptic Drugs Targeting Cerebral Presynaptic Ion Channels Reduce Cerebral Excitability Decreasing Glutamate Release

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Vanilloid (subtype 1) receptor-modulating drugs inhibit sodium channel-activated neurotransmitter release in synaptosomes by interacting with the voltage-gated sodium channel.

Vinpocetine blockade of sodium channels inhibits the rise in sodium and calcium induced by 4-aminopyridine in synaptosomes

Vinpocetine inhibits the rise in sodium and calcium induced by 4-aminopyridine, potentially explaining its anticonvulsant action.

Excitatory GABAergic synaptic potentials in the mesencephalic trigeminal nucleus of adult rat in vitro

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Characterization of the Participation of Sodium Channels on the Rise in Na+ Induced by 4-Aminopyridine (4-AP) in Synaptosomes

The TTX-sensitive fraction of neurotransmitter release evoked by 4-AP is released by exocytosis, while the TTX-insensitive fraction involves reversal of neurotransmitter transporters.