Altered Distribution of Juxtaparanodal K_v1.2 Subunits Mediates Peripheral Nerve Hyperexcitability in Type 2 Diabetes Mellitus

Abstract

Peripheral nerve hyperexcitability (PNH) is one of the distal peripheral neuropathy phenotypes often present in patients affected by type 2 diabetes mellitus (T2DM). Through in vivo and ex vivo electrophysiological recordings in db/db mice, a model of T2DM, we observed that, in addition to reduced nerve conduction velocity, db/db mice also develop PNH. By using pharmacological inhibitors, we demonstrated that the PNH is mediated by the decreased activity of K v 1-channels. In agreement with these data, we observed that the diabetic condition led to a reduced presence of the K v 1.2-subunits in juxtaparanodal regions of peripheral nerves in db/db mice and in nerve biopsies from T2DM patients. Together, these observations indicate that the T2DM condition leads to potassium channel-mediated PNH, thus identifying them as a potential drug target to treat some of the DPN related symptoms.

α-Dendrotoxin-sensitive Kv1 channels contribute to conduction failure of polymodal nociceptive C-fibers from rat coccygeal nerve

“…Scale bars in A: 100 m. *P Ͻ 0.05. of K(v)1-channels. Furthermore, the diabetic condition led to a reduced presence of the K(v)1.2-subunits in juxtaparanodal regions of peripheral nerves in db/db mice (Zenker et al 2012). Accordingly, the reduction of I DTX in DRG neurons from diabetic rats is likely due to the posttranslational regulation, such as phosphorylation of certain Kv channel subunits.…”

Nav1.7 and Nav1.8: Diabetes-induced Changes in Primary Sensory Neurons in Rats

“…1,2 Hyperglycemia is thought to be the chief cause of diabetic damage to cells of the peripheral nerves through alterations of Na + /K + activity. [3][4][5] These alterations aggregate to produce hyper-excitability of nociceptors, a key mechanism in diabetic neuropathy. A recent study, published in the Journal of Neurogastroenterology and Motility "Colonic hypersensitivity and sensitization of voltage-gated sodium channels in primary sensory neurons in rats with diabetes", 6 has observed the induction of streptozotocin (STZ) elevating colonic distension threshold, which is associated by the colonic innervated dorsal root ganglion (DRG) neurons; on which the activities and expressions of Na V 1.7 and Na V 1.8 are identified as the mechanism underlining diabetes.…”

Physiological and Pathological Functions of Mechanosensitive Ion Channels

“…The study by Simeone et al showed loss of Kv1.1 leads to enhanced synaptic release in the hippocampal CA3 region, thereby reducing spike timing precision of neurons, which provides further insight into the mechanism underling temporal lobe epilepsy [57]. Interestingly, the work by Zenker et al implicated that lower expression level of juxtaparanodal Kv1.2 and reduced nerve conduction velocity mediate peripheral nerve hyperexcitability in type 2 diabetes mellitus (T2DM) [58]. In addition, the study by Wijst and colleagues described another phenotype associated with a mutation in Kv1.1 (N255D) which results in autosomal dominant hypomagnesemia [59, 60].…”

“…These mutations impair the TRPV4 channel function and/or cell membrane location. Kv1.1 mutations cause various phenotypic seizures [56], T2DM [58] and autosomal dominant hypomagnesemia [59, 60]. Function analysis reveals these Kv1.1 mutants have defects in channel properties and/or subcellular mislocation.…”