Abstract Maladaptive plasticity involving increased expression of AMPA ‐type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPAR s is associated with side effects. As an alternative, we developed a cell‐permeable, high‐affinity (~2 nM) peptide inhibitor, Tat‐P 4 ‐(C5) 2 , of the PDZ domain protein PICK 1 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 PICK 1 dimers to form a tetrameric complex. Bivalent Tat‐P 4 ‐(C5) 2 disrupts PICK 1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPAR s with PICK 1 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. Neuropathic pain is characterized by hypersensitivity to temperature and touch as well as spontaneous outburst of pain. This study identifies a peptide that can inhibit PICK 1 and thereby interfere with insertion of excess glutamate receptor underlying the hypersensitivity in neuropathic pain.
【저자키워드】 Chemical biology, neuroscience, scaffold proteins, biopharmaceuticals, calcium permeable AMPARs, maladaptive plasticity, synaptic plasticity,