Interleukin-22 receptor 1-mediated stimulation of T-type Ca ²⁺ channels enhances sensory neuronal excitability through the tyrosine-protein kinase Lyn-dependent PKA pathway.

Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2003-

Calcium Channels, T-Type*/metabolism ; Calcium Channels, T-Type*/genetics ; src-Family Kinases*/metabolism ; Cyclic AMP-Dependent Protein Kinases*/metabolism ; Trigeminal Ganglion*/metabolism ; Sensory Receptor Cells*/metabolism ; Sensory Receptor Cells*/drug effects ; Sensory Receptor Cells*/physiology ; Receptors, Interleukin*/metabolism ; Signal Transduction*; Animals ; Male ; Mice ; Mice, Inbred C57BL ; Interleukins/metabolism

Background: Interleukin 24 (IL-24) has been implicated in the nociceptive signaling. However, direct evidence and the precise molecular mechanism underlying IL-24's role in peripheral nociception remain unclear.
Methods: Using patch clamp recording, molecular biological analysis, immunofluorescence labeling, siRNA-mediated knockdown approach and behavior tests, we elucidated the effects of IL-24 on sensory neuronal excitability and peripheral pain sensitivity mediated by T-type Ca ²⁺ channels (T-type channels).
Results: IL-24 enhances T-type channel currents (T-currents) in trigeminal ganglion (TG) neurons in a reversible and dose-dependent manner, primarily by activating the interleukin-22 receptor 1 (IL-22R1). Furthermore, we found that the IL-24-induced T-type channel response is mediated through tyrosine-protein kinase Lyn, but not its common downstream target JAK1. IL-24 application significantly activated protein kinase A; this effect was independent of cAMP and prevented by Lyn antagonism. Inhibition of PKA prevented the IL-24-induced T-current response, whereas inhibition of protein kinase C or MAPK kinases had no effect. Functionally, IL-24 increased TG neuronal excitability and enhanced pain sensitivity to mechanical stimuli in mice, both of which were suppressed by blocking T-type channels. In a trigeminal neuropathic pain model induced by chronic constriction injury of the infraorbital nerve, inhibiting IL-22R1 signaling alleviated mechanical allodynia, which was reversed by blocking T-type channels or knocking down Cav3.2.
Conclusion: Our findings reveal that IL-24 enhances T-currents by stimulating IL-22R1 coupled to Lyn-dependent PKA signaling, leading to TG neuronal hyperexcitability and pain hypersensitivity. Understanding the mechanism of IL-24/IL-22R1 signaling in sensory neurons may pave the way for innovative therapeutic strategies in pain management.
(© 2024. The Author(s).)

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82371218 National Natural Science Foundation of China; 82371218 National Natural Science Foundation of China; 82371218 National Natural Science Foundation of China; 82371218 National Natural Science Foundation of China; 82371218 National Natural Science Foundation of China; 82071236 National Natural Science Foundation of China; 82371218 National Natural Science Foundation of China; BM2013003 Jiangsu Key Laboratory of Neuropsychiatric Diseases; BM2013003 Jiangsu Key Laboratory of Neuropsychiatric Diseases; BM2013003 Jiangsu Key Laboratory of Neuropsychiatric Diseases; BM2013003 Jiangsu Key Laboratory of Neuropsychiatric Diseases; ND2022B03 Clinical Research Center of Neurological Disease; ND2022B03 Clinical Research Center of Neurological Disease; ND2022B03 Clinical Research Center of Neurological Disease; ND2022B03 Clinical Research Center of Neurological Disease; ND2022B03 Clinical Research Center of Neurological Disease; ND2022B03 Clinical Research Center of Neurological Disease; BK20211073 Natural Science Foundation of Jiangsu Province

Keywords: Interleukin 24; Pain; T-type Ca2+ channels; Trigeminal ganglion neurons; Tyrosine-protein kinase Lyn

0 (Calcium Channels, T-Type)
EC 2.7.10.2 (src-Family Kinases)
EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
0 (interleukin-22 receptor)
0 (Receptors, Interleukin)
EC 2.7.10.2 (lyn protein-tyrosine kinase)
0 (Interleukins)

Date Created: 20240603 Date Completed: 20240604 Latest Revision: 20240611

20250114

PMC11145867

10.1186/s12964-024-01688-6

38831315