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J. Biol. Chem., Vol. 277, Issue 46, 43933-43941, November 15, 2002

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The Extracellular N Terminus of the Endothelin B (ET_B) Receptor Is Cleaved by a Metalloprotease in an Agonist-dependent Process^*

Evelina Grantcharova, Jens Furkert, H. Peter Reusch^§, Hans-Willi Krell^¶, Gisela Papsdorf, Michael Beyermann, Ralf Schülein, Walter Rosenthal, and Alexander Oksche^**

From the  Forschungsinstitut für Molekulare Pharmakologie, Campus Berlin Buch, Robert-Roessle-Strasse 10, 13125 Berlin, the ^§ Institut für Klinische Pharmakologie und Toxikologie, Freie Universität Berlin, Garystrasse 5, 14195 Berlin, the ^¶ Roche-Diagnostics GmbH, Pharma-Research Penzberg, 82372 Penzberg, and the  Institut für Pharmakologie, Freie Universität Berlin, Thielallee 67-73, 14195 Berlin, Federal Republic of Germany

The extracellular N terminus of the endothelin B (ET_B) receptor is susceptible to limited proteolysis (cleavage at R64S65), but the regulation and the functional consequences of the proteolysis remain elusive. We analyzed the ET_B receptor or an ET_B-GFP fusion protein stably or transiently expressed in HEK293 cells. After incubation of cells at 4 °C, only the full-length ET_B receptor was detected at the cell surface. However, when cells were incubated at 37 °C, N-terminal cleavage was observed, provided endothelin 1 was present during the incubation. Cleavage was not inhibited by internalization inhibitors (sucrose, phenylarsine oxide). However, in cells incubated with both internalization inhibitors and metalloprotease inhibitors (batimastat, inhibitor of TNF-convertase) or metal chelators (EDTA, phenanthroline), the cleavage was blocked, indicating that metalloproteases cleave the agonist-occupied ET_B receptor at the cell surface. Functional analysis of a mutant ET_B receptor lacking the first 64 amino acids ([2-64]ET_B receptor) revealed normal functional properties, but a 15-fold reduced cell surface expression. The results suggest a role of the N-terminal proteolysis in the regulation of cell surface expression of the ET_B receptor. This is the first example of a multispanning membrane protein, which is cleaved by a metalloprotease, but retains its functional activity and overall structure.

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