Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Genetics, The University of North Carolina, Chapel Hill, NC 27599, USA.
Dev Cell. 2014 Sep 8;30(5):528-40. doi: 10.1016/j.devcel.2014.07.012.
Atypical 7-transmembrane receptors, often called decoy receptors, act promiscuously as molecular sinks to regulate ligand bioavailability and consequently temper the signaling of canonical G protein-coupled receptor (GPCR) pathways. Loss of mammalian CXCR7, the most recently described decoy receptor, results in postnatal lethality due to aberrant cardiac development and myocyte hyperplasia. Here, we provide the molecular underpinning for this proliferative phenotype by demonstrating that the dosage and signaling of adrenomedullin (Adm, gene; AM, protein)-a mitogenic peptide hormone required for normal cardiovascular development-is tightly controlled by CXCR7. To this end, Cxcr7(-/-) mice exhibit gain-of-function cardiac and lymphatic vascular phenotypes that can be reversed upon genetic depletion of adrenomedullin ligand. In addition to identifying a biological ligand accountable for the phenotypes of Cxcr7(-/-) mice, these results reveal a previously underappreciated role for decoy receptors as molecular rheostats in controlling the timing and extent of GPCR-mediated cardiac and vascular development.
非典型七跨膜受体，通常被称为诱饵受体，它们作为分子汇随机发挥作用，调节配体的生物可用性，从而调节经典 G 蛋白偶联受体 (GPCR) 信号通路。最近描述的诱饵受体哺乳动物 CXCR7 的缺失会导致心脏发育异常和心肌细胞增生，从而导致出生后死亡。在这里，我们通过证明促肾上腺皮质素释放激素 (adrenomedullin，基因；AM，蛋白）——一种正常心血管发育所必需的有丝分裂肽激素——的剂量和信号受 CXCR7 的严格控制，为这种增殖表型提供了分子基础。为此，Cxcr7(-/-) 小鼠表现出心脏和淋巴管血管的功能获得性表型，这种表型可以通过基因敲除促肾上腺皮质素释放激素配体来逆转。除了确定一个生物学配体可解释 Cxcr7(-/-) 小鼠的表型外，这些结果还揭示了诱饵受体作为分子变阻器在控制 GPCR 介导的心脏和血管发育的时间和程度方面的先前未被充分认识的作用。
