K⁺Channel Modulatory Subunits KChIP and DPP Participate in Kv4-Mediated Mechanical Pain Control

Abstract

The K ϩ channel pore-forming subunit Kv4.3 is expressed in a subset of nonpeptidergic nociceptors within the dorsal root ganglion (DRG), and knockdown of Kv4.3 selectively induces mechanical hypersensitivity, a major symptom of neuropathic pain. K ϩ channel modulatory subunits KChIP1, KChIP2, and DPP10 are coexpressed in Kv4.3 ϩ DRG neurons, but whether they participate in Kv4.3-mediated pain control is unknown. Here, we show the existence of a Kv4.3/KChIP1/KChIP2/DPP10 complex (abbreviated as the Kv4 complex) in the endoplasmic reticulum and cell surface of DRG neurons. After intrathecal injection of a gene-specific antisense oligodeoxynucleotide to knock down the expression of each component in the Kv4 complex, mechanical hypersensitivity develops in the hindlimbs of rats in parallel with a reduction in all components in the lumbar DRGs. Electrophysiological data further indicate that the excitability of nonpeptidergic nociceptors is enhanced. The expression of all Kv4 complex components in DRG neurons is downregulated following spinal nerve ligation (SNL). To rescue Kv4 complex downregulation, cDNA constructs encoding Kv4.3, KChIP1, and DPP10 were transfected into the injured DRGs (defined as DRGs with injured spinal nerves) of living SNL rats. SNL-evoked mechanical hypersensitivity was attenuated, accompanied by a partial recovery of Kv4.3, KChIP1, and DPP10 surface levels in the injured DRGs. By showing an interdependent regulation among components in the Kv4 complex, this study demonstrates that K ϩ channel modulatory subunits KChIP1, KChIP2, and DPP10 participate in Kv4.3-mediated mechanical pain control. Thus, these modulatory subunits could be potential drug targets for neuropathic pain.

Newly Discovered Action of HpTx3 from Venom of Heteropoda venatoria on Nav1.7 and Its Pharmacological Implications in Analgesia

“…The drugs that can increase A-type K v currents reverse the pain phenotype [58]. On the contrary, reduced expression of the K v 4 channels and knockdown of any component of the K v 4 channel complex in primary neurons induce mechanical hypersensitivity, a major symptom of neuropathic pain [60,61]. Oxaliplatin, a chemotherapy drug, increases nociceptive neuron excitability to result in neuropathic pain in orofacial and other regions in patients, and the down-regulation of K v 4.3 channels and I A currents may be an underlying mechanism of oxalipaltin-induced orofacial neuropatic pain [62].…”

“…Nevertheless, in our present study, HpTx3 used in several pain models showed potent analgesic activity, suggesting that the analgesic effect of HpTx3 overwhelmed the hyperalgesia it caused. This result may be explained at least partially by the fact that in the pain models the level of K v 4 channels is usually decreased [56,61,64,65]. Till now, only one model showed that the expression of K v 4 channels was increased following injury [58].…”

Etiology and Pharmacology of Neuropathic Pain

“…Spinal nerve ligation downregulated all three modulatory subunits, and their knockdown by intrathecal injection of a gene-specific antisense oligodeoxynucleotides evoked mechanical hypersensitivity. Rescue of the downregulated subunits by injection of appropriate cDNA constructs attenuated injuryinduced hypersensitivity (Kuo et al, 2017). These findings imply that targeting of regulatory subunits rather than pore-forming subunits of K + channels may lead the way to new therapeutic approaches.…”

Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors

“…When external Ca 2+ is decreased, as during repetitive synaptic activity in the molecular layer of the cerebellum, the availability of stellate cell I SA is decreased to maintain inhibitory charge transfer to Purkinje neurons [92]. It will be interesting to see whether a comparable Kv4/KChIP/Cav nanodomain signaling also exists in other neurons, as suspected recently in the case of Kv4/KChIP/DPP complexes in nociceptive DRG neurons [93], or in cardiomyocytes. Notably, in cardiomyocytes KChIP2 may form a complex with Cav1.2 [68,69], maybe in combination with Kv4 channels.…”