MicroRNA cluster miR-17-92 regulates multiple functionally related voltage-gated potassium channels in chronic neuropathic pain

• Published in: Nature communications Vol. 8; no. 1; p. 16079
• Main Authors: Sakai, Atsushi, Saitow, Fumihito, Maruyama, Motoyo, Miyake, Noriko, Miyake, Koichi, Shimada, Takashi, Okada, Takashi, Suzuki, Hidenori
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.07.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 38/35; 38/77; 38/88; 38/90; 631/337/384/331; 631/45/269/1151; 64/86; 692/617/375/1692; 82/1; 9/74; Aminopyridines; Animals; Channels; Chronic Pain - etiology; Chronic Pain - metabolism; Clusters; Down-Regulation; Ganglia, Spinal - metabolism; Humanities and Social Sciences; Hyperalgesia - etiology; Hyperalgesia - metabolism; Male; MicroRNAs; MicroRNAs - metabolism; miRNA; Modulators; multidisciplinary; Neuralgia; Neuralgia - etiology; Neuralgia - metabolism; Neuromodulation; Neurons; Neurons - metabolism; Pain; Pain perception; Phenylurea Compounds; Potassium; Potassium channels (voltage-gated); Potassium Channels, Voltage-Gated - metabolism; Potassium currents; Rats; Rats, Sprague-Dawley; Ribonucleic acid; RNA; Rodents; Science; Science (multidisciplinary); Sensory neurons; Tetrazoles
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms16079

miR-17-92 is a microRNA cluster with six distinct members. Here, we show that the miR-17-92 cluster and its individual members modulate chronic neuropathic pain. All cluster members are persistently upregulated in primary sensory neurons after nerve injury. Overexpression of miR-18a, miR-19a, miR-19b and miR-92a cluster members elicits mechanical allodynia in rats, while their blockade alleviates mechanical allodynia in a rat model of neuropathic pain. Plausible targets for the miR-17-92 cluster include genes encoding numerous voltage-gated potassium channels and their modulatory subunits. Single-cell analysis reveals extensive co-expression of miR-17-92 cluster and its predicted targets in primary sensory neurons. miR-17-92 downregulates the expression of potassium channels, and reduced outward potassium currents, in particular A-type currents. Combined application of potassium channel modulators synergistically alleviates mechanical allodynia induced by nerve injury or miR-17-92 overexpression. miR-17-92 cluster appears to cooperatively regulate the function of multiple voltage-gated potassium channel subunits, perpetuating mechanical allodynia. Dysregulation of voltage gated potassium channels is a feature of neuropathic pain. Here in a rat model the authors identify the microRNA cluster miR-17-92 as a regulator of voltage gated potassium channels in the dorsal root ganglion neurons.