Isensee, Joerg, van Cann, Marianne, Despang, Patrick ORCID: 0000-0002-5258-3653, Araldi, Dioneia ORCID: 0000-0001-8379-2901, Moeller, Katharina, Petersen, Jonas, Schmidtko, Achim, Matthes, Jan ORCID: 0000-0003-2754-1555, Levine, Jon D. and Hucho, Tim ORCID: 0000-0002-4147-9308 (2021). Depolarization induces nociceptor sensitization by Ca(V)1.2-mediated PKA-II activation. J. Cell Biol., 220 (10). NEW YORK: ROCKEFELLER UNIV PRESS. ISSN 1540-8140
Full text not available from this repository.Abstract
Depolarization drives neuronal plasticity. However, whether depolarization drives sensitization of peripheral nociceptive neurons remains elusive. By high-content screening (HCS) microscopy, we revealed that depolarization of cultured sensory neurons rapidly activates protein kinase A type II (PKA-II) in nociceptors by calcium influx through Ca(V)1.2 channels. This effect was modulated by calpains but insensitive to inhibitors of cAMP formation, including opioids. In turn, PKA-II phosphorylated Ser1928 in the distal C terminus of Ca(V)1.2, thereby increasing channel gating, whereas dephosphorylation of Ser1928 involved the phosphatase calcineurin. Patch-clamp and behavioral experiments confirmed that depolarization leads to calcium-and PKA-dependent sensitization of calcium currents ex vivo and local peripheral hyperalgesia in the skin in vivo. Our data suggest a local activity-driven feed-forward mechanism that selectively translates strong depolarization into further activity and thereby facilitates hypersensitivity of nociceptor terminals by a mechanism inaccessible to opioids.
Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||||||||||
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URN: | urn:nbn:de:hbz:38-581623 | ||||||||||||||||||||||||||||||||||||||||||||
DOI: | 10.1083/jcb.202002083 | ||||||||||||||||||||||||||||||||||||||||||||
Journal or Publication Title: | J. Cell Biol. | ||||||||||||||||||||||||||||||||||||||||||||
Volume: | 220 | ||||||||||||||||||||||||||||||||||||||||||||
Number: | 10 | ||||||||||||||||||||||||||||||||||||||||||||
Date: | 2021 | ||||||||||||||||||||||||||||||||||||||||||||
Publisher: | ROCKEFELLER UNIV PRESS | ||||||||||||||||||||||||||||||||||||||||||||
Place of Publication: | NEW YORK | ||||||||||||||||||||||||||||||||||||||||||||
ISSN: | 1540-8140 | ||||||||||||||||||||||||||||||||||||||||||||
Language: | English | ||||||||||||||||||||||||||||||||||||||||||||
Faculty: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||
Divisions: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||
Subjects: | no entry | ||||||||||||||||||||||||||||||||||||||||||||
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URI: | http://kups.ub.uni-koeln.de/id/eprint/58162 |
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