title: GDF15 regulates Kv2.1-mediated outward K+ current through the Akt/mTOR signalling pathway in rat cerebellar granule cells.
abstract: GDF15 (growth/differentiation factor 15), a novel member of the TGFβ (transforming growth factor 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. In the present paper, we report that GDF15 specifically increases the IK (delayed-rectifier outward K+ current) in rat CGNs (cerebellar granule neurons) in time- and concentration-dependent manners. The GDF15-induced amplification of the IK is mediated by the increased expression and reduced lysosome-dependent degradation of the Kv2.1 protein, the main α-subunit of the IK channel. Exposure of CGNs to GDF15 markedly induced the phosphorylation of ERK (extracellular-signal-regulated kinase), Akt and mTOR (mammalian target of rapamycin), but the GDF15-induced IK densities and increased expression of Kv2.1 were attenuated only by Akt and mTOR, and not ERK, inhibitors. Pharmacological inhibition of the Src-mediated phosphorylation of TGFβR2 (TGFβ receptor 2), not TGFβR1, abrogated the effect of GDF15 on IK amplification and Kv2.1 induction. Immunoprecipitation assays showed that GDF15 increased the tyrosine phosphorylation of TGFβRII in the CGN lysate. The results of the present study reveal a novel regulation of Kv2.1 by GDF15 mediated through the TGFβRII-activated Akt/mTOR pathway, which is a previously uncharacterized Smad-independent mechanism of GDF15 signalling.
authors.affiliation: *State Key Laboratory of Medical Neurobiology, School of Life Sciences and Institutes of Brain Science, Fudan University, Shanghai 200433, China.
authors.forename: Chang-Ying
authors.initials: CY
authors.lastname: Wang
authors.affiliation: *State Key Laboratory of Medical Neurobiology, School of Life Sciences and Institutes of Brain Science, Fudan University, Shanghai 200433, China.
authors.forename: An-Qi
authors.initials: AQ
authors.lastname: Huang
authors.affiliation: *State Key Laboratory of Medical Neurobiology, School of Life Sciences and Institutes of Brain Science, Fudan University, Shanghai 200433, China.
authors.forename: Meng-Hua
authors.initials: MH
authors.lastname: Zhou
authors.affiliation: *State Key Laboratory of Medical Neurobiology, School of Life Sciences and Institutes of Brain Science, Fudan University, Shanghai 200433, China.
authors.forename: Yan-Ai
authors.initials: YA
authors.lastname: Mei
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000502:physiology*; D055436:Growth Differentiation Factor 15 / Q000502:physiology*; D006801:Humans; D051058:Oncogene Protein v-akt / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D051669:Shab Potassium Channels / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C496988:KCNB1 protein, human; D018125:Receptors, Transforming Growth Factor beta; D051669:Shab Potassium Channels; C546842:MTOR protein, human; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II