A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain
A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain
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DOI：
10.15252/emmm.201911248
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发表时间：
2020-04-30
影响因子：
11.1
通讯作者：
Madsen, Kenneth L.
中科院分区：
文献类型：
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作者：
Christensen, Nikolaj R.;De Luca, Marta;Madsen, Kenneth L.
包括ampa型谷氨酸受体表达增加在内的适应性可塑性不良涉及多种病理，包括神经性疼痛，但直接抑制ampar会产生副作用。作为替代方案，我们开发了一种细胞渗透性高亲和力（类似于2 nM）的肽抑制剂，Tat-P-4-(C5)(2)，用于干扰PDZ结构域蛋白PICK1增加的AMPAR表达。这种亲和力部分来自Tat肽，部分来自PDZ基序的二价性，结合来自两个独立的PICK1二聚体的PDZ结构域形成四聚体复合物。二价Tat-P-4-(C5)(2)在体内破坏了支持细胞膜上的PICK1与膜蛋白的相互作用，减少了AMPARs与PICK1和ampa受体表面表达的相互作用。此外，在神经性疼痛的神经损伤模型中，Tat-P-4-(C5)(2)可减少脊髓传递，减轻机械性痛觉过敏。综上所述，我们的数据显示Tat-P-4-(C5)(2)是一种新的有希望的神经性疼痛治疗先导物，并将二价抑制剂的治疗潜力扩展到非串联蛋白-蛋白相互作用域。
Maladaptive plasticity involving increased expression of AMPA-type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell-permeable, high-affinity (similar to 2 nM) peptide inhibitor, Tat-P-4-(C5)(2), of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat-P-4-(C5)(2) disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA-receptor surface expression in vivo. Moreover, Tat-P-4-(C5)(2) administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat-P-4-(C5)(2) as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non-tandem protein-protein interaction domains.