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.
Highlights
GDF15 [growth/differentiation factor 15; known as MIC1], is a novel member of the transforming growth factor β (TGFβ) superfamily that was discovered in a screen for the conserved consensus sequences of TGFβs [1]
For the first time, we show that GDF15 may activate the TGFβR2 and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signalling pathways to increase the delayed-rectifier outward K + current (IK) amplitude, as well as the expression of Kv2.1 in cerebellar granule neuron (CGN), which may be associated with a developmental function
We observed a concomitant increase in the IK and Kv2.1 expression from 3 to 7 days in culture (DIC) (Figures 1D and 3A), which reached the maximum at 6–7 DIC [18]
Summary
GDF15 [growth/differentiation factor 15; known as MIC1 (macrophage inhibitory cytokine-1)], is a novel member of the TGFβ (transforming growth factor β) superfamily that was discovered in a screen for the conserved consensus sequences of TGFβs [1]. GDF15 plays key roles in prenatal development and the regulation of cellular responses to stress signals, inflammation and tissue repair after acute injuries in adult life [2]. GDF15 is known as a novel cardioprotective cytokine that protects the heart from ischaemia/reperfusion injury [4]. One study suggested that GDF15 was a potential support factor for neuronal synaptic development and integration during axonal elongation [9]. These data suggest that GDF15 plays a critical role in the central nervous system, the signal transduction pathways and the receptor subtypes involved are not well understand
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