Abd Alla Joshua, Reeck Kristin, Langer Andreas, Streichert Thomas, Quitterer Ursula
Department of Molecular Pharmacology, Swiss Federal Institute of Technology and University of Zurich, Winterthurerstrasse 190, Zurich, Switzerland.
Biochem Biophys Res Commun. 2009 Sep 11;387(1):186-90. doi: 10.1016/j.bbrc.2009.07.011. Epub 2009 Jul 4.
In different native tissues and cells the receptor for the vasodepressor bradykinin, B(2), forms dimers with the receptor for the vasopressor angiotensin II, AT(1). Because AT(1)/B(2) heterodimers may contribute to enhanced angiotensin II-stimulated signaling under pathophysiological conditions, we analyzed mechanisms of AT(1)/B(2) heterodimerization. We found that efficient B(2) receptor maturation was a prerequisite for heterodimerization because only the fully mature B(2) receptor was capable to interact with AT(1). To identify chaperones involved in B(2) receptor maturation and heterodimerization we performed microarray gene expression profiling of human embryonic kidney (HEK293) cells. The expression of the chaperone calreticulin was up-regulated in cells with efficient B(2) receptor maturation. Vice versa, upon down regulation of calreticulin expression by RNA interference, B(2) receptor maturation and AT(1)/B(2) receptor heterodimerization were significantly impaired. Concomitantly, the B(2) receptor-mediated enhancement of AT(1)-stimulated signaling was reduced. Thus, calreticulin enhances B(2) receptor maturation and heterodimerization with AT(1).
在不同的天然组织和细胞中，血管舒张肽缓激肽的受体B(2)与血管收缩肽血管紧张素II的受体AT(1)形成二聚体。由于在病理生理条件下，AT(1)/B(2)异源二聚体可能有助于增强血管紧张素II刺激的信号传导，我们分析了AT(1)/B(2)异源二聚化的机制。我们发现，有效的B(2)受体成熟是异源二聚化的先决条件，因为只有完全成熟的B(2)受体才能与AT(1)相互作用。为了鉴定参与B(2)受体成熟和异源二聚化的伴侣蛋白，我们对人胚肾（HEK293）细胞进行了微阵列基因表达谱分析。在B(2)受体有效成熟的细胞中，伴侣蛋白钙网蛋白的表达上调。反之，通过RNA干扰下调钙网蛋白的表达后，B(2)受体成熟和AT(1)/B(2)受体异源二聚化受到显著损害。同时，B(2)受体介导的AT(1)刺激信号增强也降低。因此，钙网蛋白增强了B(2)受体的成熟以及与AT(1)的异源二聚化。
