Hypoxia-induced sensitization of transient receptor potential vanilloid 1 involves activation of hypoxia-inducible factor-1 alpha and PKC

Abstract

The capsaicin receptor, transient receptor potential vanilloid 1 (TRPV1), acts as a polymodal detector of pain-producing chemical and physical stimuli in sensory neurons. Hyperglycemia and hypoxia are two main phenomena in diabetes associated with several complications. Although many studies on streptozotocin-induced diabetic rats indicate that early diabetic neuropathy is associated with potentiation of TRPV1 activity in dorsal root ganglion neurons, its underlying mechanism and distinctive roles of hyperglycemia and hypoxia have not been completely clarified. Here, we show that hypoxic and high glucose conditions (overnight exposure) potentiate the TRPV1 activity without affecting TRPV1 expression in both native rat sensory neurons and human embryonic kidney-derived 293 cells expressing rat or human TRPV1. Surprisingly, hypoxia was found to be a more effective determinant than high glucose, and hypoxia-inducible factor-1 alpha (HIF-1α) seemed to be involved. In addition, high glucose enhanced TRPV1 sensitization only when high glucose existed together with hypoxia. The potentiation of TRPV1 was caused by its phosphorylation of the serine residues, and translocation of protein kinase C (PKC)ε was clearly observed in the cells exposed to the hypoxic conditions in both cell types, which was inhibited by 2-methoxyestradiol, a HIF-1α inhibitor. These data suggest that hypoxia is a new sensitization mechanism for TRPV1, which might be relevant to diabetes-related complications, and also for other diseases that are associated with acute hypoxia.

Study on TRPV1-mediated mechanism for the hypersecretion of mucus in respiratory inflammation

“…The mechanism is involved in phosphorylation signaling elements downstream of this kinase. This point strongly implicates that PI3K or PKC in the signaling connecting TrkA and TRPV1 receptors are related to the activation of NGF receptor (Zhuang et al, 2004;Rathee et al, 2002;Violeta et al, 2011). Thus, we can infer that trkA-PI3K/PKC-TRPV1 signaling cascades are involved in NGF-induced sensitization.…”

“…PKC activation is a downstream event of HIF-1␣ activation, which was inhibited by a HIF-1␣ inhibitor, 2-ME2 (Yu et al, 1998). PKC is known to be associated with potentiation of TRPV1 by direct phosphorylation (Violeta et al, 2011) or by recruitment of a pool of vesicular receptors to the plasma membrane via soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent exocytosis (Morenilla-Palao et al, 2004). Thus, 2-ME2 could attenuate TRPV1 phosphorylation through inhibiting PKC activation.…”

Prolonged (9 h) poikilocapnic hypoxia (12% O2) augments cutaneous thermal hyperaemia in healthy humans

“…It is reported that hypoxia increases the sensitivity of TRPV1 channels in vitro (Ristoiu et al . ), activates eNOS and stimulates nitric oxide production (Vanin et al . ).…”

Differential effects of acute hypoxia on the activation of TRPV1 by capsaicin and acidic pH

“…c [20]. Another recent study showed facilitation of TRPV1 activity by chronic hypoxia combined with hyperglycemia [21]. In this study, TRPV1 activity was functionally upregulated via protein kinase C (PKC)e-and hypoxiainducible factor-1 alpha (HIF-1a)-dependent signaling pathway, without increases in protein expression.…”

“…The study by Ristoiu et al [21] is limited to chronic ([24 h) effect of hypoxia, and their measurements were performed under normoxic condition. In the study of anoxic effects on TRPV1, only D[Ca 2? ]…”