The Short-Term Effects of Diabetes on the Expression and Function of Tetrodotoxin-Sensitive Voltage-Gated Sodium Channels in Mouse Sensory Neurons

Abstract

Diabetic Sensory Neuropathy (DSN) presents with a constellation of sensory abnormalities, including numbness, tingling sensations, exacerbated responses to painful and non-painful stimuli, and a paradoxical loss of pain sensation. Despite the substantial burden that DSN afflicts on patients, the underlying mechanisms contributing to the pathogenesis of this disorder remains poorly understood. Particular interest has been concentrated on voltage-gated sodium (Nav) channels, especially their roles in painful forms of neuropathies in long-term diabetes. However, their possible contributions to the onset of neuropathy are still under investigation.

This project aimed at elucidating the roles of Nav channels during the early stages of DSN in sensory neurons from the dorsal root ganglion (DRG). We used cultured DRG neurons, maintained in either control (5 mM glucose) or in high glucose media (25 mM) for up to 14 days for patch-clamp electrophysiology. In addition, we used intact DRG tissues from streptozotocin (STZ)-induced diabetic mice, at one and three months after diabetes induction for the detection of Nav subunit expression. Our results indicate that DRG neurons maintained in high glucose show reduced action potential firing frequency and reduced inward currents. In addition, we observed a significant downregulation in the TTX-S Nav1.3, Nav1.6, and Nav1.7 subunits in intact DRG tissues from one-month STZ-diabetic mice. The Navβ2 subunit, which has been shown to regulate the cell surface expression of TTX-S Nav channels, also shows statistically significant reductions in its expression levels. Interestingly, after three months of STZ-induced diabetes, there was a significant upregulation in the expression level of the TTX-S Nav1.7 subunit. Taken together, our data reveal that changes causing reduction of expression and function of TTX-S Nav subunits take place at early stages in diabetes, while increased expression in Nav subunits occurs later in the disease. Therefore, our data suggest a potential role for Nav subunits in the development of the various sensory symptoms in DSN.