Monge 病患者来源星形胶质细胞内向整流钾电流下调。
Down-regulation of Inwardly Rectifying K Currents in Astrocytes Derived from Patients with Monge's Disease.
机构信息
Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, United States.
Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, United States; Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States; Rady Children's Hospital-San Diego, San Diego, CA 92123, United States.
出版信息
Neuroscience. 2018 Mar 15;374:70-79. doi: 10.1016/j.neuroscience.2018.01.016. Epub 2018 Feb 2.
Chronic mountain sickness (CMS) or Monge's disease is a disease in highlanders. These patients have a variety of neurologic symptoms such as migraine, mental fatigue, confusion, dizziness, loss of appetite, memory loss and neuronal degeneration. The cellular and molecular mechanisms underlying CMS neuropathology is not understood. In the previous study, we demonstrated that neurons derived from CMS patients' fibroblasts have a decreased expression and altered gating properties of voltage-gated sodium channel. In this study, we further characterize the electrophysiological properties of iPSC-derived astrocytes from CMS patients. We found that the current densities of the inwardly rectifying potassium (Kir) channels in CMS astrocytes (-5.7 ± 2.2 pA/pF at -140 mV) were significantly decreased as compared to non-CMS (-28.4 ± 3.4 pA/pF at -140 mV) and sea level subjects (-28.3 ± 5.3 pA/pF at -140 mV). We further demonstrated that the reduced Kir current densities in CMS astrocytes were caused by their decreased protein expression of Kir4.1 and Kir2.3 channels, while single channel properties (i.e., P, conductance) of Kir channel in CMS astrocytes were not altered. In addition, we found no significant differences of outward potassium currents between CMS and non-CMS astrocytes. As compared to non-CMS and sea level subjects, the K uptake ability in CMS astrocytes was significantly decreased. Taken together, our results suggest that down-regulation of Kir channels and the resulting decreased K uptake ability in astrocytes could be one of the major molecular mechanisms underlying the neurologic manifestations in CMS patients.
慢性山病（CMS）或 Monge 病是一种发生在高原地区人群的疾病。这些患者有多种神经系统症状，如偏头痛、精神疲劳、意识模糊、头晕、食欲不振、记忆力减退和神经元变性。CMS 神经病理学的细胞和分子机制尚不清楚。在之前的研究中，我们证明了来自 CMS 患者成纤维细胞的神经元电压门控钠离子通道的表达减少和门控特性改变。在这项研究中，我们进一步表征了来自 CMS 患者的 iPSC 衍生星形胶质细胞的电生理特性。我们发现 CMS 星形胶质细胞内向整流钾（Kir）通道的电流密度（-140 mV 时为-5.7 ± 2.2 pA/pF）与非 CMS（-140 mV 时为-28.4 ± 3.4 pA/pF）和海平面受试者（-140 mV 时为-28.3 ± 5.3 pA/pF）相比显著降低。我们进一步证明，CMS 星形胶质细胞 Kir 电流密度降低是由于 Kir4.1 和 Kir2.3 通道蛋白表达减少所致，而 Kir 通道的单通道特性（即 P、电导）在 CMS 星形胶质细胞中没有改变。此外，我们发现 CMS 和非 CMS 星形胶质细胞之间的外向钾电流没有显著差异。与非 CMS 和海平面受试者相比，CMS 星形胶质细胞的 K 摄取能力显著降低。综上所述，我们的研究结果表明，Kir 通道下调和星形胶质细胞中 K 摄取能力降低可能是 CMS 患者神经表现的主要分子机制之一。
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