Convulsant agents activate c-fos induction in both a calmodulin-dependent and calmodulin-independent manner.
Calcium acts as a second messenger and can enter neurons through several types of calcium channel. We sought to determine whether the calcium-dependent mechanisms inducing c-fos expression are identical following activation, by appropriate drugs, of L-type voltage-sensitive calcium channels or NMDA and non-NMDA receptors or following inhibition of the GABAergic system. We used primary cortical neurons and OF1 mice, and the levels of c-fos protein and c-fos mRNA were detected after treatment with the drugs by means of immunocytochemistry and in situ hybridization. The calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) abolished gamma-hexachlorocyclohexane-, Bay K 8644-, pentylenetetrazole-, and kainic acid-induced increases in c-fos expression in cultured neurons. Conversely, W-7 did not affect either NMDA- or picrotoxinin-mediated increases in c-fos expression. In mice, the pattern of protooncogene expression displayed some differences compared with cultured neurons, depending on the treatment. W-7 administered before gamma-hexachlorocyclohexane, Bay K 8644, or pentylenetetrazole blocked the expression of c-fos elicited by these compounds. However, W-7 was not able to abolish c-fos expression induced by picrotoxinin. In the animals treated with W-7 before kainic acid or NMDA administration, c-fos expression was inhibited in cerebral cortex, but it was still present in hippocampus. These results agree with the existence of diverse mechanisms transducing the calcium signals to the nucleus. Calmodulin may mediate neuronal responses depending on the route by which calcium enters the neuron, resulting in activation of different enzymes.
Barrón
S
S
Department of Pharmacology and Toxicology, CID-CSIC, Barcelona, Spain.
Tusell
J M
JM
Solà
C
C
Serratosa
J
J
D000818:Animals; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000502:physiology*; D002478:Cells, Cultured; D004396:Coloring Agents; D003292:Convulsants / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
D002147:Calmodulin; D004396:Coloring Agents; D003292:Convulsants; D016760:Proto-Oncogene Proteins c-fos; D013449:Sulfonamides; C017967:W 7