Aquilla E, Whelchel A, Knot H J, Nelson M, Posada J
Department of Molecular Physiology and Biophysics, College of Medicine, University of Vermont, Burlington, Vermont 05405, USA.
J Biol Chem. 1996 Dec 6;271(49):31572-9. doi: 10.1074/jbc.271.49.31572.
Endothelin is a 21-amino acid peptide with remarkably diverse biological properties, including potent vasoconstriction, induction of mitogenesis, and a role in the development of blood vessels. In the present study, stimulation of the endothelin B receptor was found to activate three distinct mitogen-activated protein kinase signal transduction pathways, the extracellular regulated kinase (ERK) 2, c-Jun N-terminal kinase 1 (JNK), and p38 kinase. These mitogen-activated protein kinase isozymes are thought to mediate very different biological outcomes, suggesting that the observed pattern of kinases activation may be important for the diverse biological properties of endothelin. The cytoplasmic tail of the endothelin B receptor was found to be required for activation of all three mitogen-activated protein kinases and stimulation of intracellular calcium levels. An endothelin B receptor truncated at the C-terminal tail was not able to stimulate the mitogen-activated protein kinases or increase cytosolic free calcium. Furthermore, ectopic expression of the cytoplasmic tail attenuated signaling through the wild type receptor. The observed ERK activation appeared to be mediated by heterotrimeric G proteins, since ectopic expression of a transducin alpha-subunit inhibited endothelin-stimulated ERK activation. The data suggest that the cytosolic tail of the endothelin B receptor is involved in calcium mobilization and mitogen-activated protein kinase activation via a G protein-dependent mechanism.
内皮素是一种由21个氨基酸组成的肽，具有显著多样的生物学特性，包括强力血管收缩、诱导有丝分裂以及在血管发育中起作用。在本研究中，发现刺激内皮素B受体可激活三种不同的丝裂原活化蛋白激酶信号转导途径，即细胞外调节激酶（ERK）2、c-Jun氨基末端激酶1（JNK）和p38激酶。这些丝裂原活化蛋白激酶同工酶被认为介导非常不同的生物学结果，这表明观察到的激酶激活模式可能对内皮素的多样生物学特性很重要。发现内皮素B受体的胞质尾对于所有三种丝裂原活化蛋白激酶的激活以及细胞内钙水平的刺激是必需的。在C末端截短的内皮素B受体无法刺激丝裂原活化蛋白激酶或增加胞质游离钙。此外，胞质尾的异位表达减弱了通过野生型受体的信号传导。观察到的ERK激活似乎由异源三聚体G蛋白介导，因为转导蛋白α亚基的异位表达抑制了内皮素刺激的ERK激活。数据表明，内皮素B受体的胞质尾通过G蛋白依赖性机制参与钙动员和丝裂原活化蛋白激酶激活。
