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精氨酸加压素及其受体的结构与功能研究进展
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Abstract:
精氨酸加压素(Arginine Vasopressin, AVP)，又称抗利尿激素(Antidiuretic Hormone, ADH)，是一种由下丘脑合成的环状九肽神经激素，在机体水盐平衡和血压稳态调节中发挥核心调控作用。AVP通过特异性结合G蛋白偶联受体(G Protein-Coupled Receptor, GPCR)家族成员V1受体(Vasopressin type 1 receptor, V1R)和V2受体(Vasopressin type 2 receptor, V2R)介导其生理功能：V1R主要分布于血管平滑肌，参与调控血管张力及血小板活化；V2R则高表达于肾脏集合管和远端肾小管，通过调节水通道蛋白2 (Aquaporin-2, AQP2)的膜转运介导水的重吸收。近年来，随着冷冻电子显微镜(Cryogenic Electron Microscopy, Cryo-EM)等结构生物学技术的突破，研究人员成功解析了AVP受体复合物的高分辨率三维结构，为阐明其配体识别机制和信号转导途径提供了重要的结构基础。这些研究成果不仅深化了对AVP信号通路的分子机制理解，也为基于结构的精准药物设计提供了新思路。基于V1R和V2R结构特征开发的高选择性配体有望为高血压、尿崩症等疾病的治疗提供更安全有效的治疗方案。
Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is a cyclic nonapeptide neurohormone synthesized in the hypothalamus, playing a critical role in maintaining water-electrolyte balance and blood pressure homeostasis. AVP mediates its effects through specific binding to G protein-coupled receptors (GPCRs), primarily V1R and V2R. V1R is predominantly expressed in vascular smooth muscle, where it regulates vascular tone and platelet activation, V2R is highly expressed in the renal collecting ducts and distal nephron, where V2R orchestrates water reabsorption by modulating the membrane trafficking of aquaporin-2 (AQP2). In recent years, with the breakthroughs in structural biology techniques such as Cryogenic Electron Microscopy (Cryo-EM), researchers have successfully determined the high-resolution three-dimensional structure of the arginine vasopressin (AVP) receptor complex. This achievement provides a crucial structural foundation for elucidating the ligand recognition mechanism and signal transduction pathway of the AVP receptor. These research findings not only deepen our understanding of the molecular mechanisms underlying the AVP signaling pathway but also offer novel insights into structure-based precision drug design. Highly selective ligands developed based on the structural characteristics of V1R (vasopressin receptor 1) and V2R (vasopressin receptor 2) hold great promise for providing safer and more effective therapeutic strategies for diseases such as hypertension and diabetes insipidus.
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