Bhagavan S, Ibarreta D, Ma D, Kozikowski A P, Etcheberrigaray R
Laboratory of Applied Neuroscience, Georgetown University Medical Center, Washington, DC 20007-2197, USA.
Neurobiol Dis. 1998 Sep;5(3):177-87. doi: 10.1006/nbdi.1998.0195.
Several alterations in fibroblasts of Alzheimer's disease (AD) patients have been described, including alterations in calcium regulation, protein kinase C (PKC), and potassium (K+) channels. Studies have also found reduced levels of the alpha isoform of PKC in brains and fibroblasts of AD patients. Since PKC is known to regulate ion channels, we studied K+ channel activity in fibroblasts from AD patients in the presence of (2S, 5S)-8-(1-decynyl)benzolactam (BL), a novel activator of PKC with improved selectivity for the alpha, beta, and gamma isoforms. We present evidence for restoration of normal K+ channel function, as measured by TEA-induced [Ca2+]i elevations, due to activation of PKC by BL. Representative patch-clamp data further substantiate the effect of BL on restoration of 113pS K+ channel activity. Immunoblotting analyses using an alpha-isozyme-specific PKC antibody confirm that BL-treated fibroblasts of AD patients show increased PKC activation. The present study suggests that PKC activator-based restoration of K+ channels may offer another approach to the investigation of AD pathophysiology, which in turn could lead to the development of a useful model for AD therapeutics.
阿尔茨海默病（AD）患者的成纤维细胞存在多种改变，包括钙调节、蛋白激酶C（PKC）和钾（K+）通道的改变。研究还发现，AD患者大脑和成纤维细胞中PKC的α亚型水平降低。由于已知PKC可调节离子通道，我们研究了在新型PKC激活剂（2S，5S）-8-（1-癸炔基）苯并内酰胺（BL）存在的情况下，AD患者成纤维细胞中的K+通道活性，该激活剂对α、β和γ亚型具有更高的选择性。我们提供了证据表明，通过TEA诱导的[Ca2+]i升高来衡量，由于BL激活PKC，正常K+通道功能得以恢复。代表性的膜片钳数据进一步证实了BL对113pS K+通道活性恢复的作用。使用α同工酶特异性PKC抗体进行的免疫印迹分析证实，BL处理的AD患者成纤维细胞显示出PKC激活增加。本研究表明，基于PKC激活剂恢复K+通道可能为研究AD病理生理学提供另一种方法，这反过来可能导致开发出一种有用的AD治疗模型。
