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Lamotrigine increases intracellular Ca 2+ levels and Ca 2+ /calmodulin‐dependent kinase II activation in mouse dorsal root ganglion neurones
Author(s) -
Lee E. S.,
Ryu J. H.,
Kim E.J.,
Kim G.T.,
Cho Y.W.,
Park H.J.,
Tak H.M.,
Han J.,
Kang D.
Publication year - 2013
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.12034
Subject(s) - calmodulin , dorsal root ganglion , intracellular , chemistry , microbiology and biotechnology , kinase , dorsum , biophysics , biology , biochemistry , anatomy , enzyme
Aim Lamotrigine is a neuroprotective agent that is used clinically for the treatment of seizures and neuropathic pain. A significant volume of literature has reported that lamotrigine exerts analgesic effect by blocking Ca 2+ channels. However, little is known regarding the effect of lamotrigine on the intracellular Ca 2+ concentration ([Ca 2+ ] i ). The aim of this study was to determine whether lamotrigine modulates [Ca 2+ ] i in sensory neurones. Methods Lamotrigine‐induced changes in [Ca 2+ ] i were measured in mouse dorsal root ganglion ( DRG ) neurones using the Ca 2+ ‐sensitive fluorescent indicator Fluo 3‐ AM and a confocal laser scanning microscope. Ca 2+ /calmodulin‐dependent kinase II (Ca MKII ) activation was assessed by the fluorescence intensity using immunocytochemical procedures. Results Treatment with 1, 10, 30 or 100 μ m lamotrigine transiently increased [Ca 2+ ] i in DRG neurones in a dose‐dependent manner. Treatment with 100 μ m lamotrigine induced a significant (threefold) increase in the Ca 2+ peak in the presence or absence of extracellular Ca 2+ . The lamotrigine‐induced Ca 2+ increase was abolished or decreased by the treatment with a specific PLC inhibitor (U73122), IP 3R antagonist (xestospongin C) or RyR antagonist (dantrolene). In some cells, treatment with 100 μ m lamotrigine caused a transient Ca 2+ increase, and the Ca 2+ levels quickly fell to below the basal Ca 2+ level observed prior to lamotrigine application. The decrease in basal Ca 2+ levels was blocked by the treatment with a Ca MKII inhibitor ( KN 93). Immunocytochemical analysis indicated that lamotrigine treatment increased the expression of phosphorylated Ca MKII in DRG neurones. Conclusion Treatment with lamotrigine increased [Ca 2+ ] i apparently as a result of Ca 2+ release from intracellular stores and Ca MKII activity.