Neuritin promotes neurite and spine growth in rat cerebellar granule cells via L‐type calcium channel‐mediated calcium influx

Neuritin is a neurotrophic factor that is activated by neural activity and neurotrophins. Its major function is to promote neurite growth and branching; however, the underlying mechanisms are not fully understood. To address this issue, this study investigated the effects of neuritin on neurite and spine growth and intracellular Ca(2+) concentration in rat cerebellar granule neurons (CGNs). Incubation of CGNs for 24 h with neuritin increased neurite length and spine density; this effect was mimicked by insulin and abolished by inhibiting insulin receptor (IR) or mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase (ERK) activity. Calcium imaging and western blot analysis revealed that neuritin enhanced the increase in intracellular Ca(2+) level induced by high K(+), and stimulated the cell surface expression of Ca(V)1.2 and Ca(V)1.3 α subunits of the L‐type calcium channel, which was suppressed by inhibition of IR or mitogen‐activated protein kinase kinase/ERK. Treatment with inhibitors of L‐type calcium channels, calmodulin, and calcineurin (CaN) abrogated the effects of neuritin on neurite length and spine density. A similar result was obtained by silencing nuclear factor of activated T cells c4, which is known to be activated by neuritin in CGNs. These results indicate that IR and ERK signaling as well as the Ca(2+)/CaN/nuclear factor of activated T cells c4 axis mediate the effects of neuritin on neurite and spine growth in CGNs. OPEN PRACTICES: [Image: see text] Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ [Image: see text] Cover Image for this issue: doi: 10.1111/jnc.14195.