Activation of Bradykinin B2 Receptor by Kallikrein

描述(申请人提供)：激肽释放酶激动素的重要性 健康和疾病中的心血管功能调节系统良好 已经成立了。缓激肽(BK)及其同系物Lys-BK由 血浆激肽原激肽释放酶。许多成功的治疗应用 血管紧张素转换酶(ACE；激氨酶H)抑制剂被归因于 增强BK对其7-跨膜B2受体的作用。 这项申请的目的是表明，除了肽配体，BK 激肽释放酶和其他一些丝氨酸也可以直接激活B2受体。 蛋白酶。我们在最初的研究中证明了人类激肽释放酶 在不释放激动素的情况下激活NM浓度的B2受体，这 被特定的受体阻滞剂所消除。在扩大探索性方面 实验，根据特定的目标1和2，我们将使用重组人 激肽释放酶激活人B2受体，在转基因细胞中表达 以及在构成表达天然受体的内皮细胞中。 受体的激活将通过测量花生四烯酸的释放来评估，

DESCRIPTION (provided by applicant): The importance of the kallikrein-kinin system in regulating cardiovascular function in health and disease is well established. Bradykinin (BK) and its congener, Lys-BK, are released by kallikreins from plasma kininogens. Many successful therapeutic applications of the angiotensin I converting enzyme (ACE; kininase H) inhibitors are attributed to augmenting the effects of BK on its 7-transmembrane-spanning B2 receptor. The aim of this application is to show that besides the peptide ligands, the BK B2 receptor is also directly activated by kallikreins and some other serine proteases. We demonstrated in our initial studies that human kallikrein activated the B2 receptor in nM concentrations without kinin release and this is abolished by specific receptor blocker. In expanding the exploratory experiments, according to Specific Aims 1 and 2, we will use recombinant human kallikrein to activate the human B2 receptor, expressed in transfected cells and in endothelial cells that constitutively express the native receptor. Receptor activation will be assessed by measuring arachidonic acid release,