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Topiramate modulation of kainate‐induced calcium currents is inversely related to channel phosphorylation level
Author(s) -
Ängehagen Mikael,
BenMenachem Elinor,
Shank Richard,
Rönnbäck Lars,
Hansson Elisabeth
Publication year - 2004
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 - 10.1046/j.1471-4159.2003.02186.x
Subject(s) - kainate receptor , ampa receptor , phosphorylation , glutamate receptor , ion channel , forskolin , receptor , chemistry , microbiology and biotechnology , biophysics , biology , pharmacology , medicine , biochemistry
Topiramate (TPM) is a structurally novel broad‐spectrum anticonvulsant known to modulate the activity of several ligand‐ and voltage‐gated ion channels in neurons. These include an inhibitory effect on the AMPA and kainate subtypes of glutamate receptors, mixed modulatory effects (usually positive) on some types of GABA A receptors, negative modulatory effects on some types of voltage‐gated Na + and Ca 2+ channels, and a positive modulatory effect on at least one type of K + channel. The nature of these effects at the molecular level has not been established, but two previous studies have implicated the phosphorylation state of these receptor/channel complexes as an influencing factor in the activity of TPM. Here, we report that the ability of TPM to inhibit a kainate‐induced accumulation of free Ca 2+ in cultured neurons from rat cerebral cortex is inversely related to the level of cAMP‐dependent protein kinase (cAPK) mediated phosphorylation of kainate‐activated receptors/channels. Specifically, when cell cultures were pre‐treated with forskolin or dibutyryl cAMP, indirect activators of cAPK, the activity of TPM was abolished, whereas when the cells were pre‐treated with H89, an inhibitor of cAPK, the relative activity of TPM was enhanced. The results of this study support the hypothesis that TPM binds to phosphorylation sites on AMPA and kainate receptors, but only in the dephosphorylated state and thereby exerts an allosteric modulatory effect on channel conductance.