GDF-15 enhances intracellular Ca2+ by increasing Cav1.3 expression in rat cerebellar granule neurons.
GDF-15 (growth/differentiation factor 15) is a novel member of the TGF (transforming growth factor)-β superfamily that has critical roles in the central and peripheral nervous systems. We reported previously that GDF-15 increased delayed rectifier outward K(+) currents and Kv2.1 α subunit expression through TβRII (TGF-β receptor II) to activate Src kinase and Akt/mTOR (mammalian target of rapamycin) signalling in rat CGNs (cerebellar granule neurons). In the present study, we found that treatment of CGNs with GDF-15 for 24 h increased the intracellular Ca(2+) concentration ([Ca(2+)]i) in response to membrane depolarization, as determined by Ca(2+) imaging. Whole-cell current recordings indicated that GDF-15 increased the inward Ca(2+) current (ICa) without altering steady-state activation of Ca(2+) channels. Treatment with nifedipine, an inhibitor of L-type Ca(2+) channels, abrogated GDF-15-induced increases in [Ca(2+)]i and ICa The GDF-15-induced increase in ICa was mediated via up-regulation of the Cav1.3 α subunit, which was attenuated by inhibiting Akt/mTOR and ERK (extracellular-signal-regulated kinase) pathways and by pharmacological inhibition of Src-mediated TβRII phosphorylation. Given that Cav1.3 is not only a channel for Ca(2+) influx, but also a transcriptional regulator, our data confirm that GDF-15 induces protein expression via TβRII and activation of a non-Smad pathway, and provide novel insight into the mechanism of GDF-15 function in neurons.
Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai 200433, China.
Jun-Mei
JM
Lu
Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai 200433, China.
Chang-Ying
CY
Wang
Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai 200433, China.
Changlong
C
Hu
Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai 200433, China 081023023@fudan.edu.cn yamei@fudan.edu.cn.
Yan-Jia
YJ
Fang
Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai 200433, China 081023023@fudan.edu.cn yamei@fudan.edu.cn.
Yan-Ai
YA
Mei
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055436:Growth Differentiation Factor 15 / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D055436:Growth Differentiation Factor 15; C093712:Cacna1d protein, rat; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D009543:Nifedipine; D002118:Calcium
Akt/mTOR; Cav1.3; ERK; GDF-15; TβRII; [Ca2+]i