Abstract
The role of the Slack (also known as Slo2.2, KNa1.1, or KCNT1) channel in pain-sensing is still in debate on which kind of pain it regulates. In the present study, we found that the Slack–/– mice exhibited decreased mechanical pain threshold but normal heat and cold pain sensitivity. Subsequently, X-gal staining, in situ hybridization, and immunofluorescence staining revealed high expression of the Slack channel in Isolectin B4 positive (IB4+) neurons in the dorsal root ganglion (DRG) and somatostatin-positive (SOM+) neurons in the spinal cord. Patch-clamp recordings indicated the firing frequency was increased in both small neurons in DRG and spinal SOM+ neurons in the Slack–/– mice whereas no obvious slow afterhyperpolarization was observed in both WT mice and Slack–/– mice. Furthermore, we found Kcnt1 gene expression in spinal SOM+ neurons in Slack–/– mice partially relieved the mechanical pain hypersensitivity of Slack–/– mice and decreased AP firing rates of the spinal SOM+ neurons. Finally, deletion of the Slack channel in spinal SOM+ neurons is sufficient to result in mechanical pain hypersensitivity in mice. In summary, our results suggest the important role of the Slack channel in the regulation of mechanical pain-sensing both in small neurons in DRG and SOM+ neurons in the spinal dorsal horn.
Highlights
The Slack channel (Slo2.2, KNa1.1) (Kaczmarek et al, 2017), encoded by the Kcnt1 gene, is a Na+activated potassium channel belonging to the Slo channel family (Alex Yuan et al, 2003; Salkoff et al, 2006)
All these tests were repeated using female Slack−/− mice and got similar results (Supplementary Figure 1). These results suggest that the Slack channel plays a vital role in mechanical pain sensing rather than thermal and cold pain sensing
Our present results purport that the Slack channel deletion causes mechanical hyperalgesia in mice by increasing the excitability of both small neurons in the dorsal root ganglion (DRG) and SOM+ neurons in the spinal cord but does not influence thermal and cold pain sensing
Summary
The Slack channel (Slo2.2, KNa1.1) (Kaczmarek et al, 2017), encoded by the Kcnt gene, is a Na+activated potassium channel belonging to the Slo channel family (Alex Yuan et al, 2003; Salkoff et al, 2006). The C-terminus possesses two regulators of K+ conductance (RCK) domains, essential for ligand binding and concomitant channel gating (Zhang et al, 2010). The Slack channel modulates slow afterhyperpolarization (s-AHP) following repetitive action potentials (APs) (Bhattacharjee and Kaczmarek, 2005; Wallen et al, 2007; Brown et al, 2008; Gao et al, 2008) and is associated with epilepsy (Heron et al, 2012; Ohba et al, 2015; Arai-Ichinoi et al, 2016), ALS (Zhang et al, 2017), and Fragile X syndrome (Noebels, 2015; Ferron, 2016). The Slack channel is richly expressed in the brain and dorsal root ganglia (DRG) (Bhattacharjee et al, 2002; Tamsett et al, 2009; Lu et al, 2015) suggesting its involvement in pain sensing. The Slack channel is reported expressed in IB4-positive central terminals in the spinal cord (Lu et al, 2015; Lu et al, 2021)
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