期刊
NATURE COMMUNICATIONS
卷 4, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms2673
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资金
- Netherlands Organisation for Scientific Research
- Jose Castillejo fellowship [JC2010-0196]
- Spanish Ministry of Science and Innovation
- MRC
- WCU at SNU [R31-2008-000-10103-0]
- EU IMI Europain grant
- BBSRC LOLA grant
- Wellcome Trust
- Grants-in-Aid for Scientific Research [24390200] Funding Source: KAKEN
- National Research Foundation of Korea [R31-2012-000-10103-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- Biotechnology and Biological Sciences Research Council [BB/F000227/1] Funding Source: researchfish
- Medical Research Council [G1100340, G9717869, G0901905] Funding Source: researchfish
- Versus Arthritis [20200] Funding Source: researchfish
- Wellcome Trust [101054/Z/13/Z] Funding Source: researchfish
- BBSRC [BB/F000227/1] Funding Source: UKRI
- MRC [G9717869, G0901905, G1100340] Funding Source: UKRI
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.
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