Hypoxia and high glucose activate tetrodotoxin-resistant Na+ currents through PKA and PKC

Voltage-gated sodium channels are critical for the initiation and propagation of action potentials and for the regulation of neuronal excitability. Hyperglycemia and hypoxia are two main changes in diabetes frequently associated with several complications. Although many studies on streptozotocin-induced diabetic rats indicate that early diabetic neuropathy is associated with increased amplitude and faster kinetics of sodium channels, the distinctive roles of high glucose and hypoxia have not been completely clarified. Here we show that hypoxic and high glucose conditions (overnight exposure) increase activation and inactivation of TTX-R INa in DRG neurons without affecting the level of expression. Hypoxia and high glucose alone were potent enough to induce similar or even greater sensitization than when both conditions were present, without any of them having a predominant effect. PKA is mainly responsible of the one condition effect, while under both hypoxia and high glucose PKC was also contributing to alter the kinetics, although not in a cumulative manner. These data indicate that TTX-R INa is significantly modulated under short-time exposure to hypoxia and high glucose, a mechanism which might be relevant for diabetes-related complications or other diseases associated with acute hypoxia.