Speth Robert C, Carrera Eduardo J, Bretón Catalina, Linares Andrea, Gonzalez-Reiley Luz, Swindle Jamala D, Santos Kira L, Schadock Ines, Bader Michael, Karamyan Vardan T
Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, Florida, United States of America; Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida, United States of America.
Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, Florida, United States of America; Farquhar College of Arts and Sciences, Nova Southeastern University, Fort Lauderdale, Florida, United States of America.
PLoS One. 2014 Aug 22;9(8):e105762. doi: 10.1371/journal.pone.0105762. eCollection 2014.
The recent identification of a novel binding site for angiotensin (Ang) II as the peptidase neurolysin (E.C. 3.4.24.16) has implications for the renin-angiotensin system (RAS). This report describes the distribution of specific binding of 125I-Sarcosine1, Isoleucine8 Ang II (125I-SI Ang II) in neurolysin knockout mouse brains compared to wild-type mouse brains using quantitative receptor autoradiography. In the presence of p-chloromercuribenzoic acid (PCMB), which unmasks the novel binding site, widespread distribution of specific (3 µM Ang II displaceable) 125I-SI Ang II binding in 32 mouse brain regions was observed. Highest levels of binding >700 fmol/g initial wet weight were seen in hypothalamic, thalamic and septal regions, while the lowest level of binding <300 fmol/g initial wet weight was in the mediolateral medulla. 125I-SI Ang II binding was substantially higher by an average of 85% in wild-type mouse brains compared to neurolysin knockout brains, suggesting the presence of an additional non-AT1, non-AT2, non-neurolysin Ang II binding site in the mouse brain. Binding of 125I-SI Ang II to neurolysin in the presence of PCMB was highest in hypothalamic and ventral cortical brain regions, but broadly distributed across all regions surveyed. Non-AT1, non-AT2, non-neurolysin binding was also highest in the hypothalamus but had a different distribution than neurolysin. There was a significant reduction in AT2 receptor binding in the neurolysin knockout brain and a trend towards decreased AT1 receptor binding. In the neurolysin knockout brains, the size of the lateral ventricles was increased by 56% and the size of the mid forebrain (-2.72 to +1.48 relative to Bregma) was increased by 12%. These results confirm the identity of neurolysin as a novel Ang II binding site, suggesting that neurolysin may play a significant role in opposing the pathophysiological actions of the brain RAS and influencing brain morphology.
最近鉴定出血管紧张素（Ang）II的一种新结合位点为肽酶神经溶素（E.C. 3.4.24.16），这对肾素-血管紧张素系统（RAS）具有重要意义。本报告描述了与野生型小鼠脑相比，使用定量受体放射自显影技术在神经溶素基因敲除小鼠脑中125I-肌氨酸1、异亮氨酸8血管紧张素II（125I-SI Ang II）特异性结合的分布情况。在可揭示新结合位点的对氯汞苯甲酸（PCMB）存在的情况下，观察到在32个小鼠脑区中特异性（3 μM Ang II可置换）125I-SI Ang II结合的广泛分布。下丘脑、丘脑和隔区的结合水平最高，初始湿重>700 fmol/g，而延髓中外侧的结合水平最低，初始湿重<300 fmol/g。与神经溶素基因敲除脑相比，野生型小鼠脑中125I-SI Ang II结合平均显著高出85%，这表明小鼠脑中存在一个额外的非AT1、非AT2、非神经溶素的Ang II结合位点。在PCMB存在的情况下，125I-SI Ang II与神经溶素的结合在下丘脑和腹侧皮质脑区最高，但在所有检测区域广泛分布。非AT1、非AT2、非神经溶素结合在下丘脑中也最高，但分布与神经溶素不同。神经溶素基因敲除脑中AT2受体结合显著减少，AT1受体结合有减少趋势。在神经溶素基因敲除脑中，侧脑室大小增加了56%，中脑前部大小（相对于前囟为-2.72至+1.48）增加了12%。这些结果证实了神经溶素作为一种新的Ang II结合位点的身份，表明神经溶素可能在对抗脑RAS的病理生理作用和影响脑形态方面发挥重要作用。
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