Sphingosine-1-phosphate induces Ca²⁺signaling and CXCL1 release via TRPC6 channel in astrocytes

Abstract

A biologically active lipid, sphingosine-1-phosphate (S1P) is highly abundant in blood, and plays an important role in regulating the growth, survival, and migration of many cells. Binding of the endogenous ligand S1P results in activation of various signaling pathways via G protein-coupled receptors, some of which generates Ca mobilization. In astrocytes, S1P is reported to evoke Ca signaling, proliferation, and migration; however, the precise mechanisms underlying such responses in astrocytes remain to be elucidated. Transient receptor potential canonical (TRPC) channels are Ca -permeable cation channels expressed in astrocytes and involved in Ca influx after receptor stimulation. In this study, we investigated the involvement of TRPC channels in S1P-induced cellular responses. In Ca imaging experiments, S1P at 1 μM elicited a transient increase in intracellular Ca in astrocytes, followed by sustained elevation. The sustained Ca response was markedly suppressed by S1P receptor antagonist JTE013, S1P receptor antagonist CAY10444, or non-selective TRPC channel inhibitor Pyr2. Additionally, S1P increased chemokine CXCL1 mRNA expression and release, which were suppressed by TRPC inhibitor, inhibition of Ca mobilization, MAPK pathway inhibitors, or knockdown of the TRPC channel isoform TRPC6. Taken together, these results demonstrate that S1P induces Ca signaling in astrocytes via G -coupled receptors S1P and S1P , followed by Ca influx through TRPC6 that could activate MAPK signaling, which leads to increased secretion of the proinflammatory or neuroprotective chemokine CXCL1.

TRPC6-dependent Ca2+ signaling mediates airway inflammation in response to oxidative stress via ERK pathway

“…MAPK signal pathway is implicated in inflammatory response induced by oxidative stress 31 . Furthermore, previous studies show relationships between the activation of TRPC6 and MAPK signals, which seemed to be context-dependent 47,48 . Here, we found that treatments with H 2 O 2 or O 3 evoked the release of inflammatory factors IL-6 and IL-8 via activating MAPKs (ERK, p38, JNK) (Fig.…”

Transient Receptor Potential Canonical (TRPC) Channels as Modulators of Migration and Invasion

“…TRPC6 has been shown to make a complex with TRPC3 in neuronal cells and prostate cancer epithelial cells. In astrocytes, sphingosine 1-phosphate (S1P)-evoked secretion of the C-X-C motif chemokine ligand 1 (CXCL1) is mediated through activation of TRPC6 and the mitogen-activated protein kinase (MAPK) signaling pathway [76]. Furthermore, TRPC6 is important in transforming growth factor β1 (TGFβ1) signaling in vascular smooth muscles.…”

TRPV4 is functionally expressed in oligodendrocyte precursor cells and increases their proliferation

“…Western blotting was performed as described previously [42], with slight modification. After 2 days in enriched culture, cells were lysed in RIPA buffer (Nacalai Tesque).…”