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GDF-15 regulates Kv2.1-mediated outward K+ current through Akt/mTOR signaling pathway in rat cerebellar granule cells.

Chang-Ying Wang, An-Qi Huang, Meng-Hua Zhou, Yan-Ai Mei

Biochem. J., 2014 Mar 6 , ,

VGDF-15, a novel member of the transforming growth factor-β (TGF-β) superfamily, plays critical roles in the central and peripheral nervous systems, but the signal transduction pathways and receptor subtypes involved are not well understood. Here, we report that GDF-15 specifically increases the delayed rectifier outward K+ currents (IK) in rat cerebellar granule neurons (CGNs) in time- and concentration-dependent manners. The GDF-15-induced amplification of IK is mediated by the increased expression and reduced lysosome-dependent degradation of the Kv2.1 protein, the main α-subunit of IK. Exposure of CGNs to GDF-15 markedly induced the phosphorylation of ERK, Akt, and mTOR, but the GDF-15-induced IK densities and increased expression of Kv2.1 were attenuated only by Akt and mTOR inhibitors, not ERK inhibitors. Pharmacological inhibition of the Src-mediated phosphorylation of TβRII, not TβRI, abrogated the effect of GDF-15 on IK amplification and Kv2.1 induction. Immunoprecipitation assays showed that GDF-15 increased the Tyr phosphorylation of TβRII in the CGN lysate. Our data reveal, for the first time, that the effect of GDF-15 on Kv2.1 expression might be channeled through TβRII to activate Src kinase and the Akt/mTOR pathway, which is an unanticipated role of the non-Smad-dependent pathway in the previously uncharacterized GDF-15-mediated signaling.