ACTIVATION OF MULTIPLE MITOGEN-ACTIVATED PROTEIN-KINASE SIGNAL-TRANSDUCTION PATHWAYS BY THE ENDOTHELIN-B RECEPTOR REQUIRES THE CYTOPLASMIC TAIL

Endothelin is a 21-amino acid peptide with remarkably diverse biologic al properties, including potent vasoconstriction, induction of mitogen esis, and a role in the development of blood vessels, In the present s tudy, stimulation of the endothelin B receptor was found to activate t hree distinct mitogen-activated protein kinase signal transduction pat hways, the extracellular regulated kinase (ERR) 2, c-Jun N-terminal ki nase 1 (JNK), and p38 kinase, These mitogen-activated protein kinase i sozymes are thought to mediate very different biological outcomes, sug gesting that the observed pattern of kinases activation may be importa nt for the diverse biological properties of endothelin. The cytoplasmi c tail of the endothelin B receptor was found to be required for activ ation of all three mitogen-activated protein kinases and stimulation o f intracellular calcium levels. An endothelin B receptor truncated at the C-terminal tail was not able to stimulate the mitogen-activated pr otein kinases or increase cytosolic free calcium. Furthermore, ectopic expression of the cytoplasmic Bail attenuated signaling through the m ild type receptor, The observed ERK activation appeared to be mediated by heterotrimeric G proteins, since ectopic expression of a transduci n alpha-subunit inhibited endothelin-stimulated ERK activation. The da ta suggest that the cytosolic tail of the endothelin B receptor is inv olved in calcium mobilization and mitogen-activated protein kinase act ivation via a G protein-dependent mechanism.