Negative Regulation of TRPA1 by AMPK in Primary Sensory Neurons as a Potential Mechanism of Painful Diabetic Neuropathy.

Abstract

AMPK is a widely expressed intracellular energy sensor that monitors and modulates energy expenditure. Transient receptor potential ankyrin 1 (TRPA1) channel is a widely recognized chemical and thermal sensor that plays vital roles in pain transduction. In this study, we discovered a functional link between AMPK and TRPA1 in dorsal root ganglion (DRG) neurons, in which AMPK activation rapidly resulted in downregulation of membrane-associated TRPA1 and its channel activity within minutes. Treatment with two AMPK activators, metformin or AICAR, inhibited TRPA1 activity in DRG neurons by decreasing the amount of membrane-associated TRPA1. Metformin induced a dose-dependent inhibition of TRPA1-mediated calcium influx. Conversely, in diabetic db/db mice, AMPK activity was impaired in DRG neurons, and this was associated with a concomitant increase in membrane-associated TRPA1 and mechanical allodynia. Notably, these molecular and behavioral changes were normalized following treatment with AMPK activators. Moreover, high-glucose exposure decreased activated AMPK levels and increased agonist-evoked TRPA1 currents in cultured DRG neurons, and these effects were prevented by treatment with AMPK activators. Our results identify AMPK as a previously unknown regulator of TRPA1 channels. AMPK modulation of TRPA1 could thus serve as an underlying mechanism and potential therapeutic molecular target in painful diabetic neuropathy.

• Authors: Shenglan Wang, Kimiko Kobayashi, Yoko Kogure, Hiroki Yamanaka, Satoshi Yamamoto, Hideshi Yagi, Koichi Noguchi, Yi Dai
• Journal: Diabetes (Diabetes) Vol. 67 Issue 1 Pg. 98-109 (01 2018) ISSN: 1939-327X [Electronic] United States
• PMID: 29025860 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by the American Diabetes Association.

Chemical References

• TRPA1 Cation Channel
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Animals
• Cells, Cultured
• Diabetic Neuropathies (genetics, metabolism)
• Electrophysiology
• Ganglia, Spinal (cytology, metabolism)
• HEK293 Cells
• Humans
• Immunoblotting
• Male
• Rats
• Rats, Sprague-Dawley
• Sensory Receptor Cells (metabolism)
• TRPA1 Cation Channel (genetics, metabolism)