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

Abstract

SummaryGlucose-responsive ATP-sensitive potassium channels (KATP) 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 KATP in the peripheral nervous system (PNS) are poorly understood. Here, we determine the roles of KATP in the PNS using KATP-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. KATP 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, KATP may contribute to the development of peripheral neuropathy.

Highlights

IntroductionDiabetic polyneuropathy (DPN) is the most frequent. diabetic polyneuropathy (DPN), whose prevalence in diabetic patients is up to 50% or more, is one of the most common diabetic complications and causes non-traumatic amputations of lower limbs (Nomura et al, 2018; Singleton and Smith, 2012)
Among peripheral neuropathies, diabetic polyneuropathy (DPN) is the most frequent
We demonstrate that neurite outgrowth of dorsal root ganglion (DRG) neurons was reduced by channel closers sulfonylureas

Summary

Introduction

Diabetic polyneuropathy (DPN) is the most frequent. DPN, whose prevalence in diabetic patients is up to 50% or more, is one of the most common diabetic complications and causes non-traumatic amputations of lower limbs (Nomura et al, 2018; Singleton and Smith, 2012). Voltage-gated potassium channels are known to suppress neuronal excitatory activity in the central and peripheral nervous systems and to be neuroprotective through avoiding excitotoxicity (Deng et al, 2005, 2011; Malin and Nerbonne, 2002). Another type of potassium channel, the inward-rectifying potassium channel, controls the stability of resting membrane potentials and the excitability of neurons. Under increased levels of plasma glucose, the channels close, depolarize the membrane potential, and induce an insulin release following the opening of voltage-gated calcium channels (Lang et al, 2011).

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