Role of CaMKII in nicotine-induced p38 map kinase activation

Abstract

Nitric oxide (NO), produced by neuronal NO synthase (nNOS), serves as a signaling molecule with diverse biological responses in the central nervous system (CNS). Our laboratory has shown that nicotine rapidly induced calcium-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) activation in nNOS-transfected PC12 (NPC12) cells (Nitric Oxide, 25 (2011) 344–349). In the present study, we determine whether nicotine induces JNK and p38 MAPK activation in NPC12 cells. We found that treatment of NPC12 cells with nicotine increases the phosphorylation level of p38 but not of JNK. We also show that nicotine-induced Ca2+ signaling regulates the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-p38 MAPK cascade in NPC12 cells. Nicotine stimulated transient p38 phosphorylation in NPC12 cells that was blocked by inhibition of NOS (L-NAME), the nicotinic acetylcholine receptors (mecamylamine), L-type voltage-dependent Ca2+ channels (nifedipine), or CaMKs (KN-93). However, this was not suppressed by the inhibition of CaMKK (STO-609), indicating CaMKK-CaMKI/CaMKIV cascades were not involved. These findings suggest that nicotine modulates NO-dependent calcium influx, would increase p38 phosphorylation via CaMKII activation in nNOS expressing cells.