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Presynaptic Mechanism of Action of 4‐Aminopyridine: Changes in Intracellular Free Ca 2+ Concentration and Its Relationship to B‐50 (GAP‐43) Phosphorylation
Author(s) -
Heemskerk F. M. J.,
Schrama L. H.,
Ghijsen W. E. J. M.,
Graan P. N. E.,
Lopes da Silva F. H.,
Gispen W. H.
Publication year - 1991
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1991.tb03437.x
Subject(s) - 4 aminopyridine , chemistry , intracellular , phosphorylation , mechanism of action , biophysics , mechanism (biology) , biochemistry , biology , physics , potassium channel , in vitro , quantum mechanics
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 Ca 2+ . Hence, we were interested in the relationship between changes induced by 4‐AP in the intracellular free Ca 2+ concentration ([Ca 2+ ] i ) and B‐50 phosphorylation in synaptosomes. 4‐AP (100 μ M ) elevates the [Ca 2+ ] i (as determined with fura‐2) to approximately the same extent as depolarization with 30 m M K + (from an initial resting level of 240 n M to ∼480 n M after treatment). However, the underlying mechanisms appear to be different: In the presence of 4‐AP, depolarization with K + still evoked an increase in [Ca 2+ ] i , which was additive to the elevation caused by 4‐AP. Several Ca 2+ channel antagonists (CdCl 2 , LaCl 3 , and diphenylhydantoin) inhibited the increase in B‐50 phosphorylation by 4‐AP. It is interesting that the increase in [Ca 2+ ] 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 Ca 2+ influx and B‐50 phosphorylation through voltage‐dependent channels by a mechanism dependent on Na + channel activity.