Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension

Abstract

The process of neurite extension after activation of the TrkA tyrosine kinase receptor by nerve growth factor (NGF) involves complex signaling pathways. Stimulation of sphingosine kinase 1 (SphK1), the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P), is part of the functional TrkA signaling repertoire. In this paper, we report that in PC12 cells and dorsal root ganglion neurons, NGF translocates SphK1 to the plasma membrane and differentially activates the S1P receptors S1P1 and S1P2 in a SphK1-dependent manner, as determined with specific inhibitors and small interfering RNA targeted to SphK1. NGF-induced neurite extension was suppressed by down-regulation of S1P1 expression with antisense RNA. Conversely, when overexpressed in PC12 cells, transactivation of S1P1 by NGF markedly enhanced neurite extension and stimulation of the small GTPase Rac, important for the cytoskeletal changes required for neurite extension. Concomitantly, differentiation down-regulated expression of S1P2 whose activation would stimulate Rho and inhibit neurite extension. Thus, differential transactivation of S1P receptors by NGF regulates antagonistic signaling pathways that modulate neurite extension.

LPA4/p2y9/GPR23 Mediates Rho-dependent Morphological Changes in a Rat Neuronal Cell Line

“…Neurite initiation and formation involve actin cytoskeletal changes, and as a regulator of actin reorganization, Rho GTPase has a profound effect on neuritogenesis (47). For example, S1P induces Rho-dependent neurite retraction through the S1P 2 (49,50), S1P 3 (49), and S1P 5 receptors (50,51). Several studies have also revealed a critical role for Rho and ROCK in LPA-induced neurite retraction (36,52,53), although some studies have reported Rhoindependent neurite retraction (38,54).…”

Regulating survival and development in the retina: key roles for simple sphingolipids

“…by guest, on September 1, 2018 www.jlr.org Downloaded from translocation to the plasma membrane ( 73,74 ) where its substrate, Sph, is found ( 70 ). SphK1 is responsible for S1P-mitogenic and anti-apoptotic effects; its exogenous expression induces cell proliferation and pro-survival signals whereas its downregulation activates proapoptotic events ( 75 ).…”

“…Information on the clues required for controlling its proliferation and further differentiation into photoreceptors is a prerequisite to take advantage of these cells for this regenerative purpose. S1P is involved in neuritogenesis, promoting either neurite extension or retraction, depending on the type of activated S1P receptor ( 69,73,208 ). In Xenopus retina, it participates in controlling axonal outgrowth, eliciting repulsive responses in growth cones ( 69 ).…”

PKA-Induced Internalization of Slack KNaChannels Produces Dorsal Root Ganglion Neuron Hyperexcitability

“…This is very similar to K Na reported in Xenopus spinal neurons (Dale, 1993), lamprey spinal cord neurons (Hess et al, 2007), and rat olfactory neurons (Budelli et al, 2009). These cultured embryonic neurons are ideal because they are also homogenous in their firing properties (Chen et al, 1987;Grigaliunas et al, 2002;Toman et al, 2004). Neurons are cultured in serum-free medium containing NGF.…”