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.

journal_name

Diabetes

journal_title

Diabetes

authors

Wang S,Kobayashi K,Kogure Y,Yamanaka H,Yamamoto S,Yagi H,Noguchi K,Dai Y

doi

10.2337/db17-0503

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

98-109

issue

1

eissn

0012-1797

issn

1939-327X

pii

db17-0503

journal_volume

67

pub_type

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