Striatal-enriched protein tyrosine phosphatase modulates nociception

Abstract

The information from nociceptors is processed in the dorsal horn of the spinal cord by complex circuits involving excitatory and inhibitory interneurons. It is well documented that GluN2B and ERK1/2 phosphorylation contributes to central sensitization. Striatal-enriched protein tyrosine phosphatase (STEP) dephosphorylates GluN2B and ERK1/2, promoting internalization of GluN2B and inactivation of ERK1/2. The activity of STEP was modulated by genetic (STEP knockout mice) and pharmacological (recently synthesized STEP inhibitor, TC-2153) approaches. STEP61 protein levels in the lumbar spinal cord were determined in male and female mice of different ages. Inflammatory pain was induced by complete Freund’s adjuvant injection. Behavioral tests, immunoblotting, and electrophysiology were used to analyze the effect of STEP on nociception. Our results show that both genetic deletion and pharmacological inhibition of STEP induced thermal hyperalgesia and mechanical allodynia, which were accompanied by increased pGluN2BTyr1472 and pERK1/2Thr202/Tyr204 levels in the lumbar spinal cord. Striatal-enriched protein tyrosine phosphatase heterozygous and knockout mice presented a similar phenotype. Furthermore, electrophysiological experiments showed that TC-2153 increased C fiber-evoked spinal field potentials. Interestingly, we found that STEP61 protein levels in the lumbar spinal cord inversely correlated with thermal hyperalgesia associated with age and female gender in mice. Consistently, STEP knockout mice failed to show age-related thermal hyperalgesia, although gender-related differences were preserved. Moreover, in a model of inflammatory pain, hyperalgesia was associated with increased phosphorylation-mediated STEP61 inactivation and increased pGluN2BTyr1472 and pERK1/2Thr202/Tyr204 levels in the lumbar spinal cord. Collectively, the present results underscore an important role of spinal STEP activity in the modulation of nociception.

Loss of STEP61 couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing

“…3B). From the totality of our past (Xu et al , 2015 a ; Azkona et al , 2016; Hildebrand et al , 2016; Saavedra et al , 2016) and present evidence, we conclude that loss of STEP 61 links BDNF/KCC2-dependent disinhibition to the potentiation of GluN2B NMDARs at lamina I synapses in a pathological spinal mechanism that is conserved between chronic inflammatory and neuropathic pain states.…”

“…Because disinhibition can trigger STEP 61 downregulation and STEP 61 regulates Fyn and GluN2B signalling in dorsal horn neurons (Li et al , 2015; Xu et al , 2015 a , 2018; Azkona et al , 2016), we asked whether loss of STEP 61 directly couples KCC2-dependent disinhibition to the potentiation of GluN2B NMDARs by Fyn in the ex vivo BDNF model of pathological pain. To investigate this, we explored the effects of STEP 61 antagonists and agonists on superficial dorsal horn synaptosomes from saline- versus BDNF-treated rodent spinal cords.…”

Activation of Phosphotyrosine-Mediated Signaling Pathways in the Cortex and Spinal Cord of SOD1G93A, a Mouse Model of Familial Amyotrophic Lateral Sclerosis

“…In the case of glutamate receptor subunits, it dephosphorylates the GluN2B subunit of NMDARs at Tyr1472, counteracting the activity of src kinases, and promotes the internalization from surface membranes of the NMDARs, thus contributing to the homeostatic stabilization of the excitatory synapses [ 44 – 46 ]. In the spinal cord, the role for STEP61 in the modulation of nociception and in the development of inflammatory pain has been demonstrated [ 47 , 48 ]. Li and collaborators [ 48 ] demonstrated that the hyperphosphorylation of GluN2B, fyn, and ERK2, induced by a reduction in the activity of STEP61, was critical to trigger pain hypersensitivity.…”

BDNF Driven Coupling Between KCC2 Downregulation and Fyn-Dependent Phosphorylation of GluN2B NMDA Receptors in Human Spinal Pain Processing

“…Reduction of STEP61 increases active Fyn and phosphorylation of GluN2B [79,80]. Inflammation-induced hyperalgesia leads to decrease in STEP61 activity (by both phosphorylation at serine 221 residue and cleavage) with concurrent increases in phosphorylated GluN2B in the spinal cord [82,83]. In 2019, we showed that STEP61 is significantly reduced at the superficial dorsal horn in a persistent inflammatory pain model and an ex vivo BDNF model of pathological pain processing [84].…”

“…Our finding suggests that this pathway may be conserved in these pain conditions in human males as well, although further experiments such as biochemical analysis on spine donor samples from chronic pain patients and assays to assess whether BDNF levels are elevated in patients with chronic pain must be performed for confirmation. Further, given the important role of STEP61 as the linker between disinhibition and GluN2B-mediated excitation, and its modulatory effects on all the critical elements -TrkB, Fyn and GluN2B -of the BDNF pain pathway [79,80,82,84,100] our observation that STEP61 is also downregulated at the superficial dorsal horn synapses by BDNF in human males similar to male rodents may prompt future pain research to investigate whether modulating active STEP61 levels can change pain hypersensitivity in rodents and if those findings are relevant to humans. This may be a promising avenue as directly manipulating NMDARs and BDNF-TrkB signalling can lead to various pathologies [66,[101][102][103].…”