A role for Piezo2 in EPAC1-dependent mechanical allodynia

Aberrant mechanosensation has an important role in different pain states. Here we show that Epac1 (cyclic AMP sensor) potentiation of Piezo2-mediated mechanotransduction contributes to mechanical allodynia. Dorsal root ganglia Epac1 mRNA levels increase during neuropathic pain, and nerve damage-indu...

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Published in:	Nature communications Vol. 4; no. 1; p. 1682
Main Authors:	Eijkelkamp, N, Linley, J.E., Torres, J.M., Bee, L., Dickenson, A.H., Gringhuis, M., Minett, M.S., Hong, G.S., Lee, E., Oh, U., Ishikawa, Y., Zwartkuis, F.J., Cox, J.J., Wood, J.N.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 09-04-2013 Nature Publishing Group Nature Pub. Group
Subjects:	631/378/2620/410 631/80/79/2066 Animals Base Sequence Cells, Cultured Guanine Nucleotide Exchange Factors - metabolism Guanine Nucleotide Exchange Factors - physiology Humanities and Social Sciences Hyperalgesia - etiology Ion Channels - physiology Mice Mice, Inbred C57BL Mice, Inbred CBA multidisciplinary Oligodeoxyribonucleotides Science Science (multidisciplinary) Signal Transduction
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Summary:	Aberrant mechanosensation has an important role in different pain states. Here we show that Epac1 (cyclic AMP sensor) potentiation of Piezo2-mediated mechanotransduction contributes to mechanical allodynia. Dorsal root ganglia Epac1 mRNA levels increase during neuropathic pain, and nerve damage-induced allodynia is reduced in Epac1−/− mice. The Epac-selective cAMP analogue 8-pCPT sensitizes mechanically evoked currents in sensory neurons. Human Piezo2 produces large mechanically gated currents that are enhanced by the activation of the cAMP-sensor Epac1 or cytosolic calcium but are unaffected by protein kinase C or protein kinase A and depend on the integrity of the cytoskeleton. In vivo , 8-pCPT induces long-lasting allodynia that is prevented by the knockdown of Epac1 and attenuated by mouse Piezo2 knockdown. Piezo2 knockdown also enhanced thresholds for light touch. Finally, 8-pCPT sensitizes responses to innocuous mechanical stimuli without changing the electrical excitability of sensory fibres. These data indicate that the Epac1–Piezo2 axis has a role in the development of mechanical allodynia during neuropathic pain. Mechanical allodynia describes the process whereby innocuous stimuli is perceived as being noxious and is a common symptom of neuropathic pain. Using mice deficient in the cAMP sensor Epac1, the authors in this study find that Epac1 regulates mechanical allodynia by sensitizing the mechanotransducer Piezo2.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms2673