RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose

Abstract

Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes.

Long-Term Diabetic Microenvironment Augments the Decay Rate of Capsaicin-Induced Currents in Mouse Dorsal Root Ganglion Neurons

“…However, the capsaicin-induced calcium responses are decreased, suggesting the impaired TRPV1 function in diabetic DRG neurons. Consistent with previous reports [ 25 , 26 ], we observed an increased production of ROS in DRG neurons cultured in the presence of 25 mM of glucose, simulating a hyperglycemic state. The electrophysiological recordings do not show impairment in the function of voltage-gated Ca 2+ channels in Ins2 +/Akita DRG neurons compared to control DRG neurons.…”

“…A recent study reported a RAGE (receptor for Advanced Glycation End-products)-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose, implicating RAGE in modulating TRPV1 [ 25 ], with high glucose treated DRG neurons showing potentiated capsaicin-evoked TRPV1 currents and elevated intracellular ROS accumulation [ 25 ]. In our study, high glucose treatment of DRG neurons also resulted in an increase in ROS production ( Figure 3 C).…”

Lipopolysaccharides induce a RAGE-mediated sensitization of sensory neurons and fluid hypersecretion in the upper airways

“…The potentiation of TRPV1 responses after LPS treatment could also be mediated by posttranslational modifications, independent of expression levels. As previously reported by us 23 and others 72 – 74 , cytosolic ROS potentiate CAP-evoked currents. Chuang et al 74 demonstrated that ROS mediate the modification of cysteine residues within the TRPV1 channel protein.…”

Sensory neuronal sensitisation occurs through HMGB-1–RAGE and TRPV1 in high-glucose conditions

“…Modulation of the TRP channels TRPA1 and TRPV1 has been implicated in both neuronal damage and pain in diabetic neuropathy ( Cui et al, 2014 ; Hong and Wiley, 2005 ; Khomula et al, 2013 ). TRPA1 and TRPV1 are important molecules in the sensitisation of peripheral nociceptive afferents ( Cheng and Ji, 2008 ), and TRPV1 is directly sensitised by high-glucose conditions in sensory neurons ( Lam et al, 2018 ) and during diabetes in vivo ( Hong and Wiley, 2005 ; Khomula et al, 2013 ). TRPV1 phosphorylation by PKC at S800 is key to its sensitisation ( Wang et al, 2015 ).…”

“…It should also be noted that in measuring intracellular Ca 2+ levels, albeit evoked by a TRPV1 agonist, the enhanced responses we report might represent TRPV1 sensitisation in vitro and ex vivo , but could also be attributable to changes in other ion channels. RAGE can directly contribute to PKC-dependent capsaicin-induced non-TRPV1-mediated intracellular Ca 2+ increases in high-glucose conditions ( Lam et al, 2018 ). TRPA1 is also sensitised in rat DRG immortalised neurons (50B11) in high-glucose conditions in vitro ( Hulse et al, 2015 ) and in animal models of diabetes.…”