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Distribution of non-AT(1), non-AT(2) binding of (125)I-Sarcosine(1), Isoleucine(8) angiotensin II in neurolysin knockout mouse brains

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Item Type:Article
Title:Distribution of non-AT(1), non-AT(2) binding of (125)I-Sarcosine(1), Isoleucine(8) angiotensin II in neurolysin knockout mouse brains
Creators Name:Speth, R.C. and Carrera, E.J. and Bretón, C. and Linares, A. and Gonzalez-Reiley, L. and Swindle, J.D. and Santos, K.L. and Schadock, I. and Bader, M. and Karamyan, V.T.
Abstract: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 microM 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.
Keywords:Angiotensin II, Iodine Isotopes, Metalloendopeptidases, Knockout Mice, Prosencephalon, Angiotensin Type 2 Receptor, Renin-Angiotensin System, Sarcosine, Animals, Mice
Source:PLoS ONE
ISSN:1932-6203
Publisher:Public Library of Science (U.S.A.)
Volume:9
Number:8
Page Range:e105762
Date:22 August 2014
Official Publication:https://doi.org/10.1371/journal.pone.0105762
PubMed:View item in PubMed

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