Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Department of Pediatrics, Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Pain. 2010 Oct;151(1):226-234. doi: 10.1016/j.pain.2010.07.017. Epub 2010 Aug 8.
Protein interacting with C kinase 1 (PICK1) is a PDZ-containing protein that binds to AMPA receptor (AMPAR) GluR2 subunit and protein kinase Cα (PKCα) in the central neurons. It functions as a targeting and transport protein, presents the activated form of PKCα to synaptic GluR2, and participates in synaptic AMPAR trafficking in the nervous system. Thus, PICK1 might be involved in many physiological and pathological processes triggered via the activation of AMPARs. We report herein that PICK1 knockout mice display impaired mechanical and thermal pain hypersensitivities during complete Freund's adjuvant (CFA)-induced inflammatory pain maintenance. Acute transient knockdown of spinal cord PICK1 through intrathecal injection of PICK1 antisense oligodeoxynucleotide had a similar effect. In contrast, knockout and knockdown of spinal cord PICK1 did not affect incision-induced guarding pain behaviors or mechanical or thermal pain hypersensitivities. We also found that PICK1 is highly expressed in dorsal horn, where it interacts with GluR2 and PKCα. Injection of CFA into a hind paw, but not a hind paw incision, increased PKCα-mediated GluR2 phosphorylation at Ser880 and GluR2 internalization in dorsal horn. These increases were absent when spinal cord PICK1 was deficient. Given that dorsal horn PKCα-mediated GluR2 phosphorylation at Ser880 and GluR2 internalization contribute to the maintenance of CFA-induced inflammatory pain, our findings suggest that spinal PICK1 may participate in the maintenance of persistent inflammatory pain, but not in incision-induced post-operative pain, through promoting PKCα-mediated GluR2 phosphorylation and internalization in dorsal horn neurons.
蛋白相互作用激酶 1（PICK1）是一种含有 PDZ 结构域的蛋白，它在中枢神经元中与 AMPA 受体（AMPAR）GluR2 亚基和蛋白激酶 Cα（PKCα）结合。它作为一种靶向和转运蛋白，将激活形式的 PKCα 呈现给突触 GluR2，并参与神经系统中 AMPAR 的突触转运。因此，PICK1 可能参与了许多通过 AMPAR 激活触发的生理和病理过程。我们在此报告，在完全弗氏佐剂（CFA）诱导的炎症性疼痛维持期间，PICK1 敲除小鼠表现出机械和热痛敏过度。通过鞘内注射 PICK1 反义寡核苷酸对脊髓 PICK1 的急性瞬时敲低也具有类似的效果。相比之下，敲除和敲低脊髓 PICK1 并不影响切口引起的保护疼痛行为或机械和热痛敏过度。我们还发现 PICK1 在背角中高度表达，在那里它与 GluR2 和 PKCα 相互作用。向后脚掌注射 CFA，但不向后脚掌切口注射，会增加背角中 PKCα 介导的 GluR2 磷酸化 Ser880 和 GluR2 内化。当脊髓 PICK1 缺失时，这些增加则不存在。鉴于背角 PKCα 介导的 GluR2 磷酸化 Ser880 和 GluR2 内化有助于维持 CFA 诱导的炎症性疼痛，我们的研究结果表明，脊髓 PICK1 可能通过促进背角神经元中 PKCα 介导的 GluR2 磷酸化和内化，参与持续炎症性疼痛的维持，但不参与切口引起的术后疼痛。
