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BASIC BIOLOGY

Endothelin A and Endothelin B Receptors Differ in Their Ability to Stimulate ERK1/2 Activation

Evelina Grantcharova^*,, H. Peter Reusch, Michael Beyermann, Walter Rosenthal^*, and Alexander Oksche^*,,1

^* Institut für Pharmakologie, Charité Campus Benjamin Franklin, 14195 Berlin, Germany; Forschungsinstitut für Molekulare Pharmakologie, Campus Berlin-Buch, 13125 Berlin, Germany; and Abteilung für Klinische Pharmakologie, Ruhr-Universität Bochum, 44801 Bochum, Germany

To whom requests for reprints should be addressed at ¹ Institut für Pharmakologie, Charité Campus Benjamin Franklin, Thielallee 67-73, 14195 Berlin, Germany. E-mail: alexander.oksche{at}charite.de

Abstract

Endothelin-1 (ET-1) acts on two different G protein–coupled receptors, namely the endothelin A (ET_A) and the endothelin B (ET_B) receptors. Both receptor subtypes show differences in their tissue expression and signal transduction. In the present study, we compared the ability of ET_A and ET_B receptors to stimulate extracellular signal-regulated kinase 1/2 (ERK1/2). In addition, we analyzed the role of the extracellular N terminus for ERK1/2 activation, because the ET_B receptor undergoes an agonist-dependent N-terminal proteolysis. ET-1 stimulation of HEK293 cells stably expressing the ET_A receptor induced a monophasic, but sustained ERK1/2 activation, whereas the ET_B receptor showed a biphasic ERK1/2 activation. A truncated mutant ET_B receptor, lacking the proteolytically cleaved N terminus (2-64 ET_B) revealed only a monophasic and transient ERK1/2 activation. Treatment of HEK293 2-64 ET_B cell clones with ET-1 and a synthetic NT27-64 peptide, corresponding to the N-terminally cleaved fragment of the ET_B receptor and ET-1, did not restore the biphasic activation of ERK1/2. A chimeric ET_B receptor in which the N terminus was replaced by the N terminus of the ET_A receptor elicited biphasic ERK1/2 activation. The presented data suggest that an intact N terminus of the ET_B receptor is necessary for the second phase of ERK1/2 activation. However, it appears that the length of the N terminus rather than a specific sequence motif is required for biphasic ERK1/2 activation.

Key Words: endothelin • glycosylation • G protein-coupled receptor • MAPK