PMID- 34380759 OWN - NLM STAT- MEDLINE DCOM- 20211123 LR - 20220421 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 41 IP - 42 DP - 2021 Oct 20 TI - C-Jun N-Terminal Kinase Post-Translational Regulation of Pain-Related Acid-Sensing Ion Channels 1b and 3. PG - 8673-8685 LID - 10.1523/JNEUROSCI.0570-21.2021 [doi] AB - Neuronal proton-gated acid-sensing ion channels (ASICs) participate in the detection of tissue acidosis, a phenomenon often encountered in painful pathologic diseases. Such conditions often involve in parallel the activation of various signaling pathways such as mitogen activated protein kinases (MAPKs) that ultimately leads to phenotype modifications of sensory neurons. Here, we identify one member of the MAPKs, c-Jun N-terminal kinase (JNK), as a new post-translational positive regulator of ASICs in rodent sensory neurons. Recombinant H(+)-induced ASIC currents in HEK293 cells are potently inhibited within minutes by the JNK inhibitor SP600125 in a subunit-dependent manner, targeting both rodent and human ASIC1b and ASIC3 subunits (except mouse ASIC3). The regulation by JNK of recombinant ASIC1b- and ASIC3-containing channels (homomers and heteromers) is lost on mutation of a putative phosphorylation site within the intracellular N- and the C-terminal domain of the ASIC1b and ASIC3 subunit, respectively. Moreover, short-term JNK activation regulates the activity of native ASIC1b- and ASIC3-containing channels in rodent sensory neurons and is involved in the rapid potentiation of ASIC activity by the proinflammatory cytokine TNFalpha. Local JNK activation in vivo in mice induces a short-term potentiation of the acid-induced cutaneous pain in inflammatory conditions that is partially blocked by the ASIC1-specific inhibitor mambalgin-1. Collectively, our data identify pain-related channels as novel physiological JNK substrates in nociceptive neurons and propose JNK-dependent phosphorylation as a fast post-translational mechanism of regulation of sensory-neuron-expressed ASIC1b- and ASIC3-containing channels that may contribute to peripheral sensitization and pain hypersensitivity.SIGNIFICANCE STATEMENT ASICs are a class of excitatory cation channels critical for the detection of tissue acidosis, which is a hallmark of several painful diseases. Previous work in sensory neurons has shown that ASICs containing the ASIC3 or the ASIC1b subunit are important players in different pain models. We combine here functional and pharmacological in vitro and in vivo approaches to demonstrate that the MAP Kinase JNK is a potent post-translational positive regulator, probably via direct phosphorylation, of rodent and human ASIC1b- and ASIC3-containing channels. This JNK-dependent, fast post-translational mechanism of regulation of sensory-neuron-expressed ASICs may contribute to peripheral sensitization and pain hypersensitivity. These data also identify pain-related channels as direct downstream effectors of JNK in nociceptors. CI - Copyright (c) 2021 the authors. FAU - Verkest, Clement AU - Verkest C AD - Universite Cote d'Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moleculaire et Cellulaire Laboratoire d'Excellence Canaux Ioniques d'Interet Therapeutique, Federation Hospitalo-Universitaire InovPain, 06000 Nice, France anne.baron@ipmc.cnrs.fr clement.verkest@pharma.uni-heidelberg.de. FAU - Diochot, Sylvie AU - Diochot S AD - Universite Cote d'Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moleculaire et Cellulaire Laboratoire d'Excellence Canaux Ioniques d'Interet Therapeutique, Federation Hospitalo-Universitaire InovPain, 06000 Nice, France. FAU - Lingueglia, Eric AU - Lingueglia E AD - Universite Cote d'Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moleculaire et Cellulaire Laboratoire d'Excellence Canaux Ioniques d'Interet Therapeutique, Federation Hospitalo-Universitaire InovPain, 06000 Nice, France. FAU - Baron, Anne AU - Baron A AUID- ORCID: 0000-0002-8026-6380 AD - Universite Cote d'Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moleculaire et Cellulaire Laboratoire d'Excellence Canaux Ioniques d'Interet Therapeutique, Federation Hospitalo-Universitaire InovPain, 06000 Nice, France anne.baron@ipmc.cnrs.fr clement.verkest@pharma.uni-heidelberg.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210811 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (ASIC1 protein, mouse) RN - 0 (ASIC3 protein, mouse) RN - 0 (Acid Sensing Ion Channels) RN - 0 (Anthracenes) RN - 0 (Protein Synthesis Inhibitors) RN - 1TW30Y2766 (pyrazolanthrone) RN - 6C74YM2NGI (Anisomycin) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) SB - IM MH - Acid Sensing Ion Channels/genetics/*metabolism MH - Amino Acid Sequence MH - Animals MH - Anisomycin/pharmacology MH - Anthracenes/pharmacology/therapeutic use MH - Cells, Cultured MH - Ganglia, Spinal/drug effects/metabolism MH - HEK293 Cells MH - Humans MH - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/genetics/*metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Pain/drug therapy/genetics/*metabolism MH - Protein Processing, Post-Translational/drug effects/*physiology MH - Protein Synthesis Inhibitors/pharmacology MH - Rats MH - Rats, Wistar PMC - PMC8528506 OTO - NOTNLM OT - ASICs OT - DRG neuron OT - JNK OT - TNF-alpha OT - inflammation OT - pain OT - sodium channel EDAT- 2021/08/13 06:00 MHDA- 2021/11/24 06:00 PMCR- 2022/04/20 CRDT- 2021/08/12 05:42 PHST- 2021/03/18 00:00 [received] PHST- 2021/06/29 00:00 [revised] PHST- 2021/08/03 00:00 [accepted] PHST- 2021/08/13 06:00 [pubmed] PHST- 2021/11/24 06:00 [medline] PHST- 2021/08/12 05:42 [entrez] PHST- 2022/04/20 00:00 [pmc-release] AID - JNEUROSCI.0570-21.2021 [pii] AID - JN-RM-0570-21 [pii] AID - 10.1523/JNEUROSCI.0570-21.2021 [doi] PST - ppublish SO - J Neurosci. 2021 Oct 20;41(42):8673-8685. doi: 10.1523/JNEUROSCI.0570-21.2021. Epub 2021 Aug 11.