Negative regulation of TRPA1 by AMPK in primary sensory neurons as a potential mechanism of painful diabetic neuropathy

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Abstract

AMPK is a widely expressed intracellular energy sensor that monitors andmodulates 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 membraneassociated TRPA1 and mechanical allodynia. Notably, these molecular and behavioral changeswere 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.

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Wang, S., Kobayashi, K., Kogure, Y., Yamanaka, H., Yamamoto, S., Yagi, H., … Dai, Y. (2018). Negative regulation of TRPA1 by AMPK in primary sensory neurons as a potential mechanism of painful diabetic neuropathy. Diabetes, 67(1), 98–109. https://doi.org/10.2337/db17-0503

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