Voltage-gated K⁺ channels function in macromolecular complexes with accessory subunits to regulate brain function. Here, we describe a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1)-dependent mechanism that regulates the association of the A-type K⁺ channel subunit Kv4.2 with its auxiliary subunit dipeptidyl peptidase 6 (DPP6), and thereby modulates neuronal excitability and cognitive flexibility. We show that activity-induced Kv4.2 phosphorylation triggers Pin1 binding to, and isomerization of, Kv4.2 at the pThr⁶⁰⁷-Pro motif, leading to the dissociation of the Kv4.2-DPP6 complex. We generated a novel mouse line harboring a knock-in Thr607 to Ala (Kv4.2TA) mutation that abolished dynamic Pin1 binding to Kv4.2. CA1 pyramidal neurons of the hippocampus from these mice exhibited altered Kv4.2-DPP6 interaction, increased A-type K⁺ current, and reduced neuronal excitability. Behaviorally, Kv4.2TA mice displayed normal initial learning but improved reversal learning in both Morris water maze and lever press paradigms. These findings reveal a Pin1-mediated mechanism regulating reversal learning and provide potential targets for the treatment of neuropsychiatric disorders characterized by cognitive inflexibility.

电压门控 K ⁺通道在具有辅助亚基的大分子复合物中发挥作用，调节大脑功能。在这里，我们描述了肽基脯氨酰顺反异构酶 NIMA 相互作用 1 (Pin1) 依赖性机制，该机制调节 A 型 K ⁺通道亚基 Kv4.2 与其辅助亚基二肽基肽酶 6 (DPP6) 的关联，以及从而调节神经元兴奋性和认知灵活性。我们发现，活性诱导的 Kv4.2 磷酸化会触发 Pin1 与 Kv4.2 在 pThr ⁶⁰⁷ -Pro 基序处的结合和异构化，从而导致 Kv4.2-DPP6 复合物解离。我们生成了一种新型小鼠品系，该小鼠品系含有 Thr607 敲入 Ala (Kv4.2TA) 突变，该突变废除了 Pin1 与 Kv4.2 的动态结合。这些小鼠海马 CA1 锥体神经元表现出 Kv4.2-DPP6 相互作用改变、A 型 K ⁺电流增加和神经元兴奋性降低。在行为上，Kv4.2TA 小鼠表现出正常的初始学习，但在莫里斯水迷宫和杠杆按压范例中的逆转学习有所改善。这些发现揭示了 Pin1 介导的逆转学习调节机制，并为治疗以认知不灵活为特征的神经精神疾病提供了潜在的靶点。