The Sphingosine 1-Phosphate Receptor, S1PR₁, Plays a Prominent But Not Exclusive Role in Enhancing the Excitability of Sensory Neurons

Abstract

Chi XX, Nicol GD. The sphingosine 1-phosphate receptor, S1PR 1 , plays a prominent but not exclusive role in enhancing the excitability of sensory neurons. J Neurophysiol 104: 2741-2748. First published September 15, 2010 doi:10.1152/jn.00709.2010. Sphingosine 1-phosphate (S1P) through its interaction with a family of G protein-coupled receptors (S1PR) is proving to have a significant impact on the activation of a variety of cell types, most notably those cells mediating the inflammatory response. Previously, we showed that S1P enhanced the excitability of small diameter sensory neurons, and mRNA for S1PR 1-4 was expressed in sensory neurons. These initial findings did not determine which S1PR subtype(s) mediated the increased excitability. Here, we report that exposure to the selective S1PR 1 agonist, SEW2871, produced a significant increase in excitability of some, but not all, sensory neurons. To further examine the role of S1PR 1 , neurons were treated with siRNA targeted to S1PR 1 . siRNA reduced S1PR 1 protein expression by 75% and blocked the sensitization produced by SEW2871, although some neurons remained responsive to subsequent exposure to S1P. Treatment with scramble siRNA did not alter S1PR 1 expression. Recordings from siRNA-and scramble-treated neurons suggested three distinct populations based on their sensitivities to SEW2871 and S1P. Approximately 50% of the neurons exhibited a significant increase in excitability after exposure to SEW2871 and subsequent S1P produced no additional increase; ϳ25% were not affected by SEW2871 but S1P significantly increased excitability; and ϳ25% of the neurons were not sensitized by either SEW2871 or S1P. RT-PCR measurements obtained from single neurons showed that 50% of the small diameter neurons expressed the mRNA for S1PR 1 . These results indicate that S1PR 1 plays a prominent, although not exclusive, role in mediating the enhancement of excitability produced by S1P.

GluN2B-containing NMDA receptors are upregulated in plasma membranes by the sphingosine-1-phosphate analog FTY720P

“…Taken together, the present findings support the idea that brain S1PRs regulates neuronal properties (Chun and Hartung, 2010;Lee et al, 2010;Chi and Nicol, 2010). In particular, FTY720P-induced accumulation of GluN2B at the plasma membrane may have wide-ranging functional consequences given that these receptors are implicated in a wide array of physiological and pathological functions (Pabba et al, 2014).…”

Sphingosine lysolipids in the CNS: Endogenous cannabinoid antagonists or a parallel pain modulatory system?

“…Moreover, zymosan perfusion into DRG greatly increased mechanical sensitivity, which was partially inhibited by administration of siRNA against the S1P 1 R, suggesting its involvement in the hypersensitivity response. This work supported earlier findings that S1P 1 Rs directly enhanced sensory neuron sensitivity (Chi & Nicol 2010). In that study, S1P and SEW2871 enhanced the electrical excitability of 50% of cultured small diameter sensory neurons expressing S1P 1–4 R mRNA.…”

“…In that study, S1P and SEW2871 enhanced the electrical excitability of 50% of cultured small diameter sensory neurons expressing S1P 1–4 R mRNA. However, not all excitatory effects of S1P on these neurons were S1P 1 R-mediated because approximately 25% of S1P-responsive neurons were not responsive to SEW2871 (Chi & Nicol 2010). Moreover, intracellular application of S1P, which can modulate non-GPCR targets, also produced hyperexcitability in cultured sensory neurons (Zhang et al 2006).…”

Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation

“…Moreover, S1P levels in the tumor microenvironment are greatly increased by sphingolipid metabolism in tumor cells, erythrocytes and platelets that in turn promote tumor migration, proliferation and angiogenesis [44; 49]. It is important to note that while 66.1 cells implanted and sealed into the bone do not metastasize within the 14-day test period in the absence of fracture [32] and are not likely to contribute directly to increased S1P in the spinal cord, local increases in S1P in the tumor-bearing bone could sensitize peripheral afferents [11; 30; 46] and promote the development of CIBP and spinal S1P production by provoking adaptive glutamatergic and neuroinflammatory changes in the spinal cord [51]. S1P has emerged as a key regulatory molecule in breast cancer [22; 37; 49] and thus, reduction of its levels by FTY720 and/or altering S1P signaling may reduce breast cancer growth and bone metastasis and may partially be responsible for the decrease in CIBP, supporting its clinical use in metastatic cancers.…”