C-Jun N-Terminal Kinase Post-Translational Regulation of Pain-Related Acid-Sensing Ion Channels 1b and 3

• DOI: 10.1523/jneurosci.0570-21.2021
• Publication Date: 2021-08-11T17:50:24Z
• Authors: Clément Verkest; Sylvie Diochot; Eric Lingueglia; Anne Baron
• Keywords: Acid-sensing ion channel; c-jun

Neuronal proton-gated acid-sensing ion channels (ASICs) participate in the detection of tissue acidosis, a phenomenon often encountered painful pathologic diseases. Such conditions involve parallel activation various signaling pathways such as mitogen activated protein kinases (MAPKs) that ultimately leads to phenotype modifications sensory neurons. Here, we identify one member MAPKs, c-Jun N-terminal kinase (JNK), new post-translational positive regulator ASICs rodent Recombinant H + -induced ASIC currents HEK293 cells are potently inhibited within minutes by JNK inhibitor SP600125 subunit-dependent manner, targeting both and human ASIC1b ASIC3 subunits (except mouse ASIC3). The regulation recombinant ASIC1b- ASIC3-containing (homomers heteromers) is lost on mutation putative phosphorylation site intracellular N- C-terminal domain subunit, respectively. Moreover, short-term regulates activity native neurons involved rapid potentiation proinflammatory cytokine TNFα. Local vivo mice induces acid-induced cutaneous pain inflammatory partially blocked ASIC1-specific mambalgin-1. Collectively, our data pain-related novel physiological substrates nociceptive propose JNK-dependent fast mechanism sensory-neuron-expressed may contribute peripheral sensitization hypersensitivity. SIGNIFICANCE STATEMENT class excitatory cation critical for which hallmark several Previous work has shown containing or subunit important players different models. We combine here functional pharmacological vitro approaches demonstrate MAP Kinase potent regulator, probably via direct phosphorylation, channels. This JNK-dependent, These also downstream effectors nociceptors.