Neuritin Activates Insulin Receptor Pathway to Up-regulate Kv4.2-mediated Transient Outward K+ Current in Rat Cerebellar Granule Neurons

Neuritin is a new neurotrophic factor discovered in a screen to identify genes involved in activity-dependent synaptic plasticity. Neuritin also plays multiple roles in the process of neural development and synaptic plasticity. The receptors for binding neuritin and its downstream signaling effectors, however, remain unclear. Here, we report that neuritin specifically increases the densities of transient outward K+ currents (IA) in rat cerebellar granule neurons (CGNs) in a time- and concentration-dependent manner. Neuritin-induced amplification of IA is mediated by increased mRNA and protein expression of Kv4.2, the main α-subunit of IA. Exposure of CGNs to neuritin markedly induces phosphorylation of ERK (pERK), Akt (pAkt), and mammalian target of rapamycin (pmTOR). Neuritin-induced IA and increased expression of Kv4.2 are attenuated by ERK, Akt, or mTOR inhibitors. Unexpectedly, pharmacological blockade of insulin receptor, but not the insulin-like growth factor 1 receptor, abrogates the effect of neuritin on IA amplification and Kv4.2 induction. Indeed, neuritin activates downstream signaling effectors of the insulin receptor in CGNs and HeLa. Our data reveal, for the first time, an unanticipated role of the insulin receptor in previously unrecognized neuritin-mediated signaling. Background: Neuritin is a new neurotrophic factor. The receptors for binding neuritin and its downstream signaling effectors, however, remain unclear. Results: Neuritin increases Kv4.2-mediated IA in rat cerebellar granule neurons by activating the insulin receptor pathway. Conclusion: Neuritin may act as a ligand of the insulin receptor. Significance: Our findings reveal an unanticipated role of the insulin receptor in previously unrecognized neuritin-mediated signaling.