Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
J Neurosci. 2011 May 18;31(20):7424-40. doi: 10.1523/JNEUROSCI.0936-11.2011.
Output properties of neurons are greatly shaped by voltage-gated ion channels, whose biophysical properties and localization within axodendritic compartments serve to significantly transform the original input. The hyperpolarization-activated current, I(h), is mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and plays a fundamental role in influencing neuronal excitability by regulating both membrane potential and input resistance. In neurons such as cortical and hippocampal pyramidal neurons, the subcellular localization of HCN channels plays a critical functional role, yet mechanisms controlling HCN channel trafficking are not fully understood. Because ion channel function and localization are often influenced by interacting proteins, we generated a knock-out mouse lacking the HCN channel auxiliary subunit, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Eliminating expression of TRIP8b dramatically reduced I(h) expression in hippocampal pyramidal neurons. Loss of I(h)-dependent membrane voltage properties was attributable to reduction of HCN channels on the neuronal surface, and there was a striking disruption of the normal expression pattern of HCN channels in pyramidal neuron dendrites. In heterologous cells and neurons, absence of TRIP8b increased HCN subunit targeting to and degradation by lysosomes. Mice lacking TRIP8b demonstrated motor learning deficits and enhanced resistance to multiple tasks of behavioral despair with high predictive validity for antidepressant efficacy. We observed similar resistance to behavioral despair in distinct mutant mice lacking HCN1 or HCN2. These data demonstrate that interaction with the auxiliary subunit TRIP8b is a major mechanism underlying proper expression of HCN channels and I(h) in vivo, and suggest that targeting I(h) may provide a novel approach to treatment of depression.
神经元的输出特性受电压门控离子通道极大地影响，其生物物理特性和在轴突树突隔室中的定位显著改变了原始输入。超极化激活电流 I(h)由超极化激活环核苷酸门控 (HCN) 通道介导，通过调节膜电位和输入电阻来影响神经元兴奋性，起着至关重要的作用。在皮质和海马锥体神经元等神经元中，HCN 通道的亚细胞定位起着关键的功能作用，但控制 HCN 通道运输的机制尚未完全了解。由于离子通道的功能和定位通常受相互作用蛋白的影响，我们生成了一种缺乏 HCN 通道辅助亚基四肽重复序列结合 Rab8b 相互作用蛋白 (TRIP8b) 的敲除小鼠。消除 TRIP8b 的表达可显著降低海马锥体神经元中的 I(h)表达。I(h)依赖的膜电压特性的丧失归因于神经元表面 HCN 通道的减少，并且 HCN 通道在锥体神经元树突中的正常表达模式出现明显中断。在异源细胞和神经元中，缺乏 TRIP8b 会增加 HCN 亚基向溶酶体的靶向和降解。缺乏 TRIP8b 的小鼠表现出运动学习缺陷，并对多种行为绝望任务具有增强的抗性，具有很高的抗抑郁疗效预测性。我们在缺乏 HCN1 或 HCN2 的不同突变小鼠中观察到类似的对行为绝望的抗性。这些数据表明，与辅助亚基 TRIP8b 的相互作用是 HCN 通道和 I(h) 在体内正确表达的主要机制，并表明靶向 I(h)可能为治疗抑郁症提供一种新方法。
