Depolarization induces nociceptor sensitization by CaV1.2-mediated PKA-II activation

Jörg Isensee; Marianne van Cann; Patrick Despang; Dioneia Araldi; Katharina Moeller; Jonas Petersen; Achim Schmidtko; Jan Matthes; Jon D. Levine; Tim Hucho

doi:10.1083/jcb.202002083

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Depolarization induces nociceptor sensitization by CaV1.2-mediated PKA-II activation

Journal article

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Depolarization induces nociceptor sensitization by CaV1.2-mediated PKA-II activation

Jörg Isensee, Marianne van Cann, Patrick Despang, Dioneia Araldi, Katharina Moeller, Jonas Petersen, Achim Schmidtko, Jan Matthes, Jon D. Levine and Tim Hucho

The Journal of cell biology, Vol.220(10), e202002083

10/04/2021

DOI: 10.1083/jcb.202002083

PMID: 34431981

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Abstract

Isensee et al. describe a peripheral mechanism by which excitation of nociceptive sensory neurons leads to pain hypersensitivity. Depolarization of nociceptors results in cAMP-independent activation of type II protein kinase A (PKA-II) by calcium influx through CaV1.2 channels, which in turn modulates calcium channel activity. 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 CaV1.2 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 CaV1.2, 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.

Cell Signaling

Neuroscience

Details

Title: Subtitle: Depolarization induces nociceptor sensitization by CaV1.2-mediated PKA-II activation
Creators: Jörg Isensee - University of Cologne
Marianne van Cann - University of Cologne
Patrick Despang - University of Cologne
Dioneia Araldi - University of California, San Francisco
Katharina Moeller - University of Cologne
Jonas Petersen - Goethe University Frankfurt
Achim Schmidtko - Goethe University Frankfurt
Jan Matthes - University of Cologne
Jon D. Levine - University of California, San Francisco
Tim Hucho - University of Cologne
Resource Type: Journal article
Publication Details: The Journal of cell biology, Vol.220(10), e202002083
DOI: 10.1083/jcb.202002083
PMID: 34431981
ISSN: 0021-9525
eISSN: 1540-8140
Publisher: Rockefeller University Press
Grant note: ; 3622/0787/11 / ; 0316177A / ;
Alternative title: Depolarization induces nociceptor sensitization
Language: English
Date published: 10/04/2021
Academic Unit: Neuroscience and Pharmacology
Record Identifier: 9985177947702771

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