Kir6.2-deficient mice develop somatosensory dysfunction and axonal loss in the peripheral nerves

Hiromi Nakai-Shimoda; Tatsuhito Himeno; Tetsuji Okawa; Emiri Miura-Yura; Sachiko Sasajima; Makoto Kato; Yuichiro Yamada; Yoshiaki Morishita; Shin Tsunekawa; Yoshiro Kato; Yusuke Seino; Rieko Inoue; Masaki Kondo; Susumu Seino; Keiko Naruse; Koichi Kato; Hiroki Mizukami; Jiro Nakamura; Hideki Kamiya

doi:10.1016/j.isci.2021.103609

Kir6.2-deficient mice develop somatosensory dysfunction and axonal loss in the peripheral nerves

iScience. 2021 Dec 11;25(1):103609. doi: 10.1016/j.isci.2021.103609. eCollection 2022 Jan 21.

Authors

Hiromi Nakai-Shimoda¹, Tatsuhito Himeno^{1

2}, Tetsuji Okawa³, Emiri Miura-Yura¹, Sachiko Sasajima¹, Makoto Kato¹, Yuichiro Yamada¹, Yoshiaki Morishita¹, Shin Tsunekawa¹, Yoshiro Kato¹, Yusuke Seino⁴, Rieko Inoue¹, Masaki Kondo¹, Susumu Seino⁵, Keiko Naruse⁶, Koichi Kato⁷, Hiroki Mizukami⁸, Jiro Nakamura^{1

2}, Hideki Kamiya¹

Affiliations

¹ Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan.
² Department of Innovative Diabetes Therapy, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan.
³ Department of Endocrinology, Gifu Prefectural Tajimi Hospital, Tajimi 507-8522, Japan.
⁴ Division of Endocrinology and Metabolism, Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake 470-1192, Aichi, Japan.
⁵ Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe 650-0047, Japan.
⁶ Department of Internal Medicine, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, Japan.
⁷ Department of Medicine, Aichi Gakuin University School of Pharmacy, Nagoya 464-8650, Japan.
⁸ Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.

Abstract

Glucose-responsive ATP-sensitive potassium channels (K_ATP) are expressed in a variety of tissues including nervous systems. The depolarization of the membrane potential induced by glucose may lead to hyperexcitability of neurons and induce excitotoxicity. However, the roles of K_ATP in the peripheral nervous system (PNS) are poorly understood. Here, we determine the roles of K_ATP in the PNS using K_ATP-deficient (Kir6.2-deficient) mice. We demonstrate that neurite outgrowth of dorsal root ganglion (DRG) neurons was reduced by channel closers sulfonylureas. However, a channel opener diazoxide elongated the neurite. K_ATP subunits were expressed in mouse DRG, and expression of certain subunits including Kir6.2 was increased in diabetic mice. In Kir6.2-deficient mice, the current perception threshold, thermal perception threshold, and sensory nerve conduction velocity were impaired. Electron microscopy revealed a reduction of unmyelinated and small myelinated fibers in the sural nerves. In conclusion, K_ATP may contribute to the development of peripheral neuropathy.

Keywords: Cellular neuroscience; Molecular neuroscience; Sensory neuroscience.