K+Channel Modulatory Subunits KChIP and DPP Participate in Kv4-Mediated Mechanical Pain Control.
The K+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+channel modulatory subunits KChIP1, KChIP2, and DPP10 are coexpressed in Kv4.3+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+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.SIGNIFICANCE STATEMENTNeuropathic pain, a type of moderate to severe chronic pain resulting from nerve injury or disorder, affects 6.9%-10% of the global population. However, less than half of patients report satisfactory pain relief from current treatments. K+channels, which act to reduce nociceptor activity, have been suggested to be novel drug targets for neuropathic pain. This study is the first to show that K+channel modulatory subunits KChIP1, KChIP2, and DPP10 are potential drug targets for neuropathic pain because they form a channel complex with the K+channel pore-forming subunit Kv4.3 in a subset of nociceptors to selectively inhibit mechanical hypersensitivity, a major symptom of neuropathic pain.
Institute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.
Yen-Ling
YL
Kuo
Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan.|Department of Anesthesiology, Mackay Memorial Hospital, Taipei 104, Taiwan, and.|Mackay Junior College of Medicine, Nursing, and Management, Taipei 112, Taiwan.
Jen-Kun
0000-0003-2384-7856
JK
Cheng
Institute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.
Wen-Hsien
WH
Hou
Institute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.
Yu-Cheng
YC
Chang
Institute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.
Po-Hao
0000-0001-8317-0475
PH
Du
Institute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.
Jhao-Jun
JJ
Jian
Department of Anesthesiology, Mackay Memorial Hospital, Taipei 104, Taiwan, and.
Ruey-Horng
RH
Rau
Institute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.
Jung-Hui
0000-0003-4886-998X
JH
Yang
Institute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.
Cheng-Chang
0000-0002-6692-9942
CC
Lien
Institute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan, mltsaur@ym.edu.tw.
Meei-Ling
0000-0002-2874-5034
ML
Tsaur
D000818:Animals; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D059226:Nociceptive Pain / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism*; D014110:Touch
D051605:Kv Channel-Interacting Proteins; D051672:Shal Potassium Channels; C523849:DPP10 protein, rat; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
DPP10; DRG; KChIP1; KChIP2; Kv4.3