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  3. Interleukin-22 receptor 1-mediated stimulation of T-type Ca2+ channels enhances sensory neuronal excitability through the tyrosine-protein kinase Lyn-dependent PKA pathway

Interleukin-22 receptor 1-mediated stimulation of T-type Ca2+ channels enhances sensory neuronal excitability through the tyrosine-protein kinase Lyn-dependent PKA pathway

  • Cell Commun Signal. 2024 Jun 3;22(1):307. doi: 10.1186/s12964-024-01688-6.
Hua Cai # 1,  Siyu Chen # 1 2,  Yufang Sun # 2 3,  Tingting Zheng 1,  Yulu Liu 1,  Jin Tao 4 5 6,  Yuan Zhang 7 8 9
Affiliations

Affiliations

  • 1 Clinical Research Center of Neurological Disease, Department of Geriatrics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, P.R. China.
  • 2 Department of Physiology and Neurobiology & Centre for Ion Channelopathy, Suzhou Medical College of Soochow University, Suzhou, 215123, P.R. China.
  • 3 Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, 215123, P.R. China.
  • 4 Department of Physiology and Neurobiology & Centre for Ion Channelopathy, Suzhou Medical College of Soochow University, Suzhou, 215123, P.R. China. taoj@suda.edu.cn.
  • 5 Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, 215123, P.R. China. taoj@suda.edu.cn.
  • 6 MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, 215123, P.R. China. taoj@suda.edu.cn.
  • 7 Clinical Research Center of Neurological Disease, Department of Geriatrics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, P.R. China. yuanzhang@suda.edu.cn.
  • 8 Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, 215123, P.R. China. yuanzhang@suda.edu.cn.
  • 9 MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, 215123, P.R. China. yuanzhang@suda.edu.cn.
  • # Contributed equally.
PMID: 38831315 DOI: 10.1186/s12964-024-01688-6
Abstract

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 CA2+ 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.

Keywords

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

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