Redox Signal-mediated Enhancement of the Temperature Sensitivity of Transient Receptor Potential Melastatin 2 (TRPM2) Elevates Glucose-induced Insulin Secretion from Pancreatic Islets

Makiko Kashio,Makoto Tominaga

doi:10.1074/jbc.m115.649913

Abstract

Transient receptor potential melastatin 2 (TRPM2) is a thermosensitive Ca(2+)-permeable cation channel expressed by pancreatic β cells where channel function is constantly affected by body temperature. We focused on the physiological functions of redox signal-mediated TRPM2 activity at body temperature. H2O2, an important molecule in redox signaling, reduced the temperature threshold for TRPM2 activation in pancreatic β cells of WT mice but not in TRPM2KO cells. TRPM2-mediated [Ca(2+)]i increases were likely caused by Ca(2+) influx through the plasma membrane because the responses were abolished in the absence of extracellular Ca(2+). In addition, TRPM2 activation downstream from the redox signal plus glucose stimulation enhanced glucose-induced insulin secretion. H2O2 application at 37 °C induced [Ca(2+)]i increases not only in WT but also in TRPM2KO β cells. This was likely due to the effect of H2O2 on KATP channel activity. However, the N-acetylcysteine-sensitive fraction of insulin secretion by WT islets was increased by temperature elevation, and this temperature-dependent enhancement was diminished significantly in TRPM2KO islets. These data suggest that endogenous redox signals in pancreatic β cells elevate insulin secretion via TRPM2 sensitization and activity at body temperature. The results in this study could provide new therapeutic approaches for the regulation of diabetic conditions by focusing on the physiological function of TRPM2 and redox signals.

Highlights

Transient receptor potential melastatin 2 (TRPM2) is a temperature-sensitive Ca2ϩ-permeable ion channel involved in glucose-induced insulin secretion
We focused on the physiological function of TRPM2 sensitization in glucose-induced insulin secretion from pancreatic islets and the effect of temperature on this process
Temperature Sensitivity in Pancreatic ␤ Cells Was Enhanced by H2O2 Treatment—We have reported previously that the temperature threshold for TRPM2 activation was reduced from a supraphysiological to a physiological temperature range by H2O2, a kind of reactive oxygen species (ROS), termed “sensitization,” involved in macrophage functions [9]

Summary

Background

Transient receptor potential melastatin 2 (TRPM2) is a temperature-sensitive Ca2ϩ-permeable ion channel involved in glucose-induced insulin secretion. The N-acetylcysteine-sensitive fraction of insulin secretion by WT islets was increased by temperature elevation, and this temperature-dependent enhancement was diminished significantly in TRPM2KO islets These data suggest that endogenous redox signals in pancreatic ␤ cells elevate insulin secretion via TRPM2 sensitization and activity at body temperature. We explored its involvement in cytokine release and the phagocytic activity of mouse peritoneal macrophages, in which the binding of pathogen-associated molecular patterns to Tolllike receptors activates NADPH oxidase and elicits the production of ROS for microbicidal activity These findings illustrate that TRPM2 activity at body temperature could be regulated by endogenous redox signals. We have reported previously that TRPM2 has high Ca2ϩ permeability and is expressed in pancreatic ␤ cells [7] It regulates insulin secretion evoked by glucose or glucose together with incretin hormones at body temperature [13, 14]. We focused on the physiological function of TRPM2 sensitization in glucose-induced insulin secretion from pancreatic islets and the effect of temperature on this process

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION