Abstract
Two-pore domain K+ (K2P) channels generate K+ leak current, which serves a vital role in controlling and modulating neuronal excitability. This diverse family of K+ channels exhibit distinct expression and function across neuronal tissues. TWIK-related spinal cord K+ channel (TRESK) is a K2P channel with a particularly enriched role in sensory neurons and in vivo pain pathways. Here, we explored the role of TRESK across molecularly distinct sensory neuron populations and assessed its contribution to different sensory modalities. We found TRESK mRNA only in select populations of C- and A-δ nociceptors, in addition to low threshold D-hair afferents. Neurons from mice in which TRESK has been ablated demonstrated marked hyperexcitability, which was amplified under inflammatory challenge. Detailed behavioral phenotyping of TRESK knockout mice revealed specific deficits in somatosensory processing of noxious and non-noxious stimuli. These results demonstrate novel roles of TRESK in somatosensory processing and offer important information to those wishing to target the channel for therapeutic means.
Highlights
Two-pore domain K+ (K2P) channels are the molecular mediators of K+ leak, which is essential for proper neuronal function
In human and rodent tissue, TWIK-related spinal cord K+ channel (TRESK) is highly enriched in sensory ganglia of the dorsal root ganglion (DRG) and trigeminal ganglion (TG) (Dobler et al, 2007; Lafrenière et al, 2010)
Within small diameter neurons (≤25 μm) that likely represent unmyelinated C-fibers, TRESK was present in 72.43 ± 1.25% of neurons that bound the lectin IB4, but only 29.43 ± 8.50% of calcitonin gene related peptide (CGRP) positive neurons (peptidergic nociceptors; Nagy and Hunt, 1982; FIGURE 1 | KCNK18 mRNA in mouse trigeminal ganglion (TG)
Summary
Two-pore domain K+ (K2P) channels are the molecular mediators of K+ leak, which is essential for proper neuronal function. Activation of trigeminal nociceptors innervating the dural meninges likely underlies the headache phase of migraine (Weir and Cader, 2011), offering a plausible locus of action of the mutation due to the enrichment of TRESK in these afferents (Lafrenière et al, 2010). Such data is leading to increased efforts to target channel activity as an analgesic strategy (Wright et al, 2013; Bruner et al, 2014; Sehgal et al, 2014; Mathie and Veale, 2015)
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