Sphingosine 1-phosphate enhances the excitability of rat sensory neurons through activation of sphingosine 1-phosphate receptors 1 and/or 3

Abstract

BackgroundSphingosine-1-phosphate (S1P) is a bioactive sphingolipid that acts through a family of five G-protein-coupled receptors (S1PR1–5) and plays a key role in regulating the inflammatory response. Our previous studies demonstrated that rat sensory neurons express the mRNAs for all five S1PRs and that S1P increases neuronal excitability primarily, but not exclusively, through S1PR1. This raises the question as to which other S1PRs mediate the enhanced excitability.MethodsIsolated sensory neurons were treated with either short-interfering RNAs (siRNAs) or a variety of pharmacological agents targeted to S1PR1/R2/R3 to determine the role(s) of these receptors in regulating neuronal excitability. The excitability of isolated sensory neurons was assessed by using whole-cell patch-clamp recording to measure the capacity of these cells to fire action potentials (APs).ResultsAfter siRNA treatment, exposure to S1P failed to augment the excitability. Pooled siRNA targeted to S1PR1 and R3 also blocked the enhanced excitability produced by S1P. Consistent with the siRNA results, pretreatment with W146 and CAY10444, selective antagonists for S1PR1 and S1PR3, respectively, prevented the S1P-induced increase in neuronal excitability. Similarly, S1P failed to augment excitability after pretreatment with either VPC 23019, which is a S1PR1 and R3 antagonist, or VPC 44116, the phosphonate analog of VPC 23019. Acute exposure (10 to 15 min) to either of the well-established functional antagonists, FTY720 or CYM-5442, produced a significant increase in the excitability. Moreover, after a 1-h pretreatment with FTY720 (an agonist for S1PR1/R3/R4/R5), neither SEW2871 (S1PR1 selective agonist) nor S1P augmented the excitability. However, after pretreatment with CYM-5442 (selective for S1PR1), SEW2871 was ineffective, but S1P increased the excitability of some, but not all, sensory neurons.ConclusionsThese results demonstrate that the enhanced excitability produced by S1P is mediated by activation of S1PR1 and/or S1PR3.

S1PR3 mediates itch and pain via distinct TRP channel-dependent pathways

“…416 417 But how, mechanistically, does this dose-dependent and selective activation of itch versus pain by S1P 418 occur? A number of studies have generally implicated calcium-activated chloride and voltage-dependent 419 potassium and sodium channels as being important for S1P-evoked neuronal excitation (Zhang et al,420 2006a; Camprubi-Robles et al, 2013; Li et al, 2015). Here we show for the first time that both TRPA1 and 421 TRPV1 play a key role in S1P-evoked AP firing in distinct subsets of somatosensory neurons and in itch 422 and pain behaviors.…”

Sphingosine 1‐phosphate receptor 1 is required for retinal ganglion cell survival after optic nerve trauma

“…; Li et al . ), to our knowledge, their possible involvement in adult CNS neuron response has not been investigated after trauma.…”

“…S1P signal can thus result in the activation of intracellular effectors exerting beneficial or deleterious effects on neurite extension, depending on the relative level of S1PR1 and S1PR2/S1PR5 at the plasma membrane. Although S1PRs are expressed in CNS neurons (Ceccom et al 2014;Kempf et al 2014;Silva et al 2014;Li et al 2015), to our knowledge, their possible involvement in adult CNS neuron response has not been investigated after trauma. In this study, we set out to determine if S1P-S1PRs contributed to CNS adult neuronal cell death and axonal growth after traumatic injury by using the optic nerve crush model in adult mice.…”

The TrkA receptor mediates experimental thermal hyperalgesia produced by nerve growth factor: Modulation by the p75 neurotrophin receptor

“…Intraplantar injection of S1P itself causes acute hyperalgesia (Doyle et al, 2011b), apparently through activation of the S1PR 1 receptor isoform (Mair et al, 2011) and S1P also mediates, via a GPCR (Zhang et al, 2006a), the acute hyperexcitability of isolated sensory neurons caused by NGF (Zhang et al, 2006b). This latter effect involves S1PR 1 and S1PR 3 (Li et al, 2015), receptors also implicated both in neurite extension caused by NGF exposure in vitro (Toman et al, 2004) and in chronic neuropathic pain from chemotherapeutics (Janes et al, 2014; also see Patti et al, 2012). Initial hydrolysis by sphingomyelinases of sphingomyelin(s), a phospholipid found in many neuronal plasma membranes (Strichartz, 1977), produces ceramide(s) which is subsequently converted to sphingosine, and then to S1P by the enzyme sphingosine kinase (SphK).…”