Mouse semaphorin H induces PC12 cell neurite outgrowth activating Ras- mitogen-activated protein kinase signaling pathway via Ca2+ influx

Abstract

We recently showed that mouse semaphorin H (MSH), a secreted semaphorin molecule, acts as a chemorepulsive factor on sensory neurites. In this study, we found for the first time that MSH induces neurite outgrowth in PC12 cells in a dose-dependent manner. Comparison of Ras-mitogen-activated protein kinase (MAPK) signaling pathways between MSH and nerve growth factor (NGF) revealed that these pathways are crucial for MSH action as well as NGF. K- 252a, an inhibitor of tyrosine autophosphorylation of tyrosine kinase receptors (Trks), did not inhibit the action of MSH, suggesting that MSH action occurs via a different receptor than NGF. L- and N-types of voltage- dependent Ca2+ channel blockers, diltiazem and ω-conotoxin, inhibited MSH- induced neurite outgrowth and MAPK phosphorylation in a Ca2+-dependent manner. A transient elevation in intracellular Ca2+ level was observed upon MSH stimulation. These findings suggest that extracellular Ca2+ influx, followed by activation of the Ras-MAPK signaling pathway, is required for MSH induced PC12 cell neurite outgrowth.