Upregulation of TRESK Channels Contributes to Motor and Sensory Recovery after Spinal Cord Injury

Abstract

TWIK (tandem-pore domain weak inward rectifying K+)-related spinal cord K+ channel (TRESK), a member of the two-pore domain K+ channel family, is abundantly expressed in dorsal root ganglion (DRG) neurons. It is well documented that TRESK expression is changed in several models of peripheral nerve injury, resulting in a shift in sensory neuron excitability. However, the role of TRESK in the model of spinal cord injury (SCI) has not been fully understood. This study investigates the role of TRESK in a thoracic spinal cord contusion model, and in transgenic mice overexpressed with the TRESK gene (TGTRESK). Immunostaining analysis showed that TRESK was expressed in the dorsal and ventral neurons of the spinal cord. The TRESK expression was increased by SCI in both dorsal and ventral neurons. TRESK mRNA expression was upregulated in the spinal cord and DRG isolated from the ninth thoracic (T9) spinal cord contusion rats. The expression was significantly upregulated in the spinal cord below the injury site at acute time points (6, 24, and 48 h) after SCI (p < 0.05). In addition, TRESK expression was markedly increased in DRGs below and adjacent to the injury site. TRESK was expressed in inflammatory cells. In addition, the number and fluorescence intensity of TRESK-positive neurons increased in the dorsal and ventral horns of the spinal cord after SCI. TGTRESK SCI mice showed faster paralysis recovery and higher mechanical threshold compared to wild-type (WT)-SCI mice. TGTRESK mice showed lower TNF-α concentrations in the blood than WT mice. In addition, IL-1β concentration and apoptotic signals in the caudal spinal cord and DRG were significantly decreased in TGTRESK SCI mice compared to WT-SCI mice (p < 0.05). These results indicate that TRESK upregulated following SCI contributes to the recovery of paralysis and mechanical pain threshold by suppressing the excitability of motor and sensory neurons and inflammatory and apoptotic processes.

The Special One: Architecture, Physiology and Pharmacology of the TRESK Channel

“…Both peptides act as important neurotransmitters and are involved in pain transmission and in (neuro)inflammation [66,67]. Thus, TRESK function might play an important role in distinct inflammatory processes as well, which is strengthened by many different studies [33,[68][69][70][71]. Endogenous mediators of inflammation like arachidonic acid are able to inhibit TRESK channels at low micromolar concentrations [25,72].…”

“…In vivo induced inflammation by injection of complete Freund's adjuvant leads to reduced expression of several K 2P channels including TRESK on rat DRG neurons [62,70]. On the other hand, overexpression of TRESK reduces not only the release of substance P and CGRP but also further inflammatory mediators like TNFα or IL1β [71]. Transgenic mice benefit from overexpressing TRESK in a model of spinal cord injury featuring accelerated paralysis recovery and reduced apoptotic signaling in the spinal cord [71].…”

“…On the other hand, overexpression of TRESK reduces not only the release of substance P and CGRP but also further inflammatory mediators like TNFα or IL1β [71]. Transgenic mice benefit from overexpressing TRESK in a model of spinal cord injury featuring accelerated paralysis recovery and reduced apoptotic signaling in the spinal cord [71].…”

What Is the Role of 2-Pore Domain Potassium Channels (K2P) in Pain?

“…89 In contrast, in a model of spinal cord injury, TRESK upregulation in the ventral and dorsal horns and DRG promoted functional recovery by suppressing the excitability of motor and sensory neurons and reducing inflammation and apoptosis. 90 Gene sequence variants of the KCNK18 gene encoding TRESK have been linked with migraine. 48,91 Some of these Two-pore domain potassium (K2P) channels consist of 2 subunits, each with 4 helical transmembrane domains (TM1-TM4), 2 pore-forming loops (P1 and P2), and a large intracellular region.…”

Contribution of Neuronal and Glial Two-Pore-Domain Potassium Channels in Health and Neurological Disorders

“…several areas of the central nervous system, including the cortex, periaqueductal gray (PAG), and dorsal horn of the spinal cord [47]. Spinal nerve ligation in mice to induce neuropathic pain is associated with TRESK upregulation in the superficial dorsal horn [48], and overexpressing TRESK in such animals alleviated their hyperalgesia, inflammation, and neuronal apoptosis [49,50]. These results suggest that TRESK in the spinal cord plays an essential role in pain perception, which needs to be confirmed in electrophysiological studies.…”