Wang Yue, Nicol G D, Clapp D Wade, Hingtgen Cynthia M
Departments of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, 46202, USA.
J Neurophysiol. 2005 Dec;94(6):3670-6. doi: 10.1152/jn.00489.2005. Epub 2005 Aug 10.
Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by tumor formation. People with NF1 also can experience more intense painful responses to stimuli, such as minor trauma, than normal. NF1 results from a heterozygous mutation of the NF1 gene, leading to decreased levels of neurofibromin, the protein product of the NF1 gene. Neurofibromin is a guanosine triphosphatase activating protein (GAP) for Ras and accelerates the conversion of active Ras-GTP to inactive Ras-GDP; therefore mutation of the NF1 gene frequently results in an increase in activity of the Ras transduction cascade. Using patch-clamp electrophysiological techniques, we examined the excitability of capsaicin-sensitive sensory neurons isolated from the dorsal root ganglia of adult mice with a heterozygous mutation of the Nf1 gene (Nf1+/-), analogous to the human mutation, in comparison to wildtype sensory neurons. Sensory neurons from adult Nf1+/- mice generated a more than twofold higher number of action potentials in response to a ramp of depolarizing current as wild-type neurons. Consistent with the greater number of action potentials, Nf1+/- neurons had lower firing thresholds, lower rheobase currents, and shorter firing latencies than wild-type neurons. Interestingly, nerve growth factor augmented the excitability of wild-type neurons in a concentration-related manner but did not further alter the excitability of the Nf1+/- sensory neurons. These data clearly suggest that GAPs, such as neurofibromin, can play a key role in the excitability of nociceptive sensory neurons. This increased excitability may explain the painful conditions experienced by people with NF1.
1型神经纤维瘤病（NF1）是一种常见的以肿瘤形成为特征的遗传性疾病。与正常人相比，患有NF1的人对诸如轻微创伤等刺激也会经历更强烈的疼痛反应。NF1是由NF1基因的杂合突变引起的，导致神经纤维瘤蛋白水平降低，神经纤维瘤蛋白是NF1基因的蛋白质产物。神经纤维瘤蛋白是一种针对Ras的鸟苷三磷酸酶激活蛋白（GAP），可加速活性Ras-GTP向无活性Ras-GDP的转化；因此，NF1基因的突变经常导致Ras转导级联反应的活性增加。我们使用膜片钳电生理技术，研究了与人类突变类似的、具有Nf1基因杂合突变（Nf1+/-）的成年小鼠背根神经节中分离出的辣椒素敏感感觉神经元的兴奋性，并与野生型感觉神经元进行了比较。与野生型神经元相比，成年Nf1+/-小鼠的感觉神经元在去极化电流斜坡刺激下产生的动作电位数量高出两倍多。与动作电位数量增加一致，Nf1+/-神经元的放电阈值更低、基强度电流更低，并且放电潜伏期比野生型神经元更短。有趣的是，神经生长因子以浓度相关的方式增强了野生型神经元的兴奋性，但并未进一步改变Nf1+/-感觉神经元的兴奋性。这些数据清楚地表明，诸如神经纤维瘤蛋白之类的GAP在伤害性感觉神经元的兴奋性中可能起关键作用。这种兴奋性增加可能解释了NF1患者所经历的疼痛状况。
