Slick (Kcnt2) Sodium-Activated Potassium Channels Limit Peptidergic Nociceptor Excitability and Hyperalgesia

Abstract

The Slick (Kcnt2) sodium-activated potassium (KNa) channel is a rapidly gating and weakly voltage-dependent and sodium-dependent potassium channel with no clearly defined physiological function. Within the dorsal root ganglia (DRGs), we show Slick channels are exclusively expressed in small-sized and medium-sized calcitonin gene–related peptide (CGRP)-containing DRG neurons, and a pool of channels are localized to large dense-core vesicles (LDCV)-containing CGRP. We stimulated DRG neurons for CGRP release and found Slick channels contained within CGRP-positive LDCV translocated to the neuronal membrane. Behavioral studies in Slick knockout (KO) mice indicated increased basal heat detection and exacerbated thermal hyperalgesia compared with wild-type littermate controls during neuropathic and chronic inflammatory pain. Electrophysiologic recordings of DRG neurons from Slick KO mice revealed that Slick channels contribute to outward current, propensity to fire action potentials (APs), and to AP properties. Our data suggest that Slick channels restrain the excitability of CGRP-containing neurons, diminishing pain behavior after inflammation and injury.

Transcriptomics Analysis of Porcine Caudal Dorsal Root Ganglia in Tail Amputated Pigs Shows Long-Term Effects on Many Pain-Associated Genes

“…Significant reductions in DRG neuronal expression of genes coding for multiple voltage-gated K + channel subunits were observed in response to tail amputation in the microarray study (i.e., KCNA4, KCNG4, KCNQ3, KCNH6, KCNV1, KCNT2). The observation of a down-regulation of these voltage-gated channel sub-unit transcripts is consistent with a large number of reports in previous neuropathic pain studies in rodents (22, 23, 119, 120, 125–142). In addition, DRG neuronal transcripts for two K + two-domain pore (K 2 P) leak channels (KCNK1 and KCNK10) were also shown to be consistently down regulated in response to peripheral nerve resection after tail amputation.…”

“…Inhibitory GABAergic dorsal horn neurons synapse with the central terminals of primary sensory neurons to pre-synaptically modulate primary sensory afferent input to the CNS. The removal of GABAergic control can lead to increase in heightened pain sensitivity (e.g., an exaggerated response to painful stimuli and/or response to innocuous tactile or thermal stimuli) due to disinhibition (151), and this has been demonstrated experimentally in a number of rodent models of neuropathic pain following peripheral nerve injury by complete nerve transection, chronic constriction and part nerve ligation (142–159). In the current microarray study, tail amputation produced a marked and sustained reduction in the transcript expression of two ionotropic ( GABRB2, GABRB3 ) and two metabotropic ( GABBR1, GABBR2 ) GABA receptor subunits.…”

The local translation of KNa in dendritic projections of auditory neurons and the roles of KNa in the transition from hidden to overt hearing loss

“…K Na 1.1 and K Na 1.2 have been localized in the medial nucleus of the trapezoid body (MNTB) in the auditory brainstem and shown to regulate spike timing [24, 25] and in peripheral neurons in the dorsal root ganglion (DRG), where they regulate nociceptive responses [23, 26, 27]. However, Kcnt1 and Kcnt2 mRNA have recently been localized in SGN cell bodies [21].…”

Sodium-activated potassium channels shape peripheral auditory function and activity of the primary auditory neurons in mice

“…K Na 1.1 and K Na 1.2 are regulated by intracellular Na + and, in neurons of the MNTB, manipulation of intracellular Na + concentration and application of pharmacological activators indicate that K Na activity improves the fidelity of timing at high action potential frequencies 15 . Outside of the central nervous system, K Na 1.1 and/or 1.2 are expressed in the primary sensory neurons of the dorsal root ganglion neurons 16–20 . Genetic deletion of either K Na 1.1 19 or K Na 1.2 20 results in increased excitability of distinct populations of dorsal root ganglion (DRG) neurons and exacerbated nociceptor responses.…”

“…Outside of the central nervous system, K Na 1.1 and/or 1.2 are expressed in the primary sensory neurons of the dorsal root ganglion neurons 16–20 . Genetic deletion of either K Na 1.1 19 or K Na 1.2 20 results in increased excitability of distinct populations of dorsal root ganglion (DRG) neurons and exacerbated nociceptor responses. These findings, expression of K Na channels in primary sensory neurons and contribution of K Na activity to signal encoding in the central auditory system, motivate examination of their role in regulating the function of the peripheral auditory system.…”