Phosphorylation of the AMPARs regulated by protein kinase C (PKC) and protein interacting with C-kinase 1 (PICK1) contribute to orofacial neuropathic pain

Fei Liu; Yu-Han Zhang; Yan-Yan Zhang; Jiu Lin; Ya-Jing Liu; Yue-Ling Li; Zhong-Han Fang; Hong-Lin Liao; Hang Wang; Jie-Fei Shen

doi:10.1016/j.brainres.2023.148578

Phosphorylation of the AMPARs regulated by protein kinase C (PKC) and protein interacting with C-kinase 1 (PICK1) contribute to orofacial neuropathic pain

Brain Res. 2023 Dec 1:1820:148578. doi: 10.1016/j.brainres.2023.148578. Epub 2023 Sep 12.

Authors

Affiliations

¹ State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
² State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China. Electronic address: shenjiefei@scu.edu.cn.

PMID: 37709161
DOI: 10.1016/j.brainres.2023.148578

Abstract

The α-amino-3-hydroxy-5-methylisoxazole-4-isoxazolepropionic acid receptor (AMPAR) has been recognized to play a vital role in the development of neuropathic pain. Recent studies have indicated that protein kinase C (PKC) and protein interacting with C-kinase 1 (PICK1) are involved in the phosphorylation of AMPARs. However, whether PKC and PICK1 were involved in the AMPAR phosphorylation in the trigeminal ganglion (TG) to participate in orofacial neuropathic pain remains enigmatic. A behavioral test was utilized to evaluate the head withdrawal threshold (HWT) after chronic constriction injury of the infraorbital nerve (CCI-ION). The distribution and expression of GluA1, GluA2, PKC, and PICK1 were examined in the trigeminal ganglion (TG) by immunofluorescence, real-time reverse transcription-quantitative polymerase chain reaction, immunoblotting, and co-immunoprecipitation. Intra-ganglionic injections of drugs were performed to investigate the regulation mechanism. The present study demonstrated that CCI-ION-induced mechanical allodynia was maintained over at least 21 days. GluA1 and GluA2 were mainly expressed in the neurons. Trigeminal nerve injury potentiated the phosphorylation of GluA1, GluA2, and PKC in the TG, which was prevented by inhibiting PKC with chelerythrine chloride. Additionally, PICK1 colocalized and interacted with GluA2 in the TG. Following blocking PICK1 with FSC-231, the phosphorylation of GluA2 decreased. Finally, inhibition of PKC and PICK1 both alleviated mechanical allodynia in the whisker pad of CCI-ION mice. In conclusion, activation of PKC and PICK1 contribute to orofacial allodynia by regulating AMPAR phosphorylation in the TG of male mice, which provides potential therapeutic targets for alleviating orofacial neuropathic pain.

Keywords: Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors; Orofacial neuropathic pain; Protein interacting with C-kinase 1; Protein kinase C; Trigeminal ganglion; Trigeminal nerve injury.