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J. Biol. Chem., Vol. 278, Issue 32, 30283-30293, August 8, 2003
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From the Institute of Pharmacology, University of Vienna, Währinger Strasse 13A, A-1090 Vienna, Austria
The carboxyl terminus (C-tail) of G protein-coupled receptors is divergent in length and structure and may represent an individualized cytoplasmic domain. By progressively truncating the A1 adenosine receptor, a Gi/o-coupled receptor with short cytoplasmic stretches, we identify two inherent functions of the C-tail, namely a role in receptor export from the endoplasmic reticulum (ER) and a role in G protein coupling. Deletion of the last 22 and 26 amino acids (of 36) reduced and completely abolished surface expression of the receptor, respectively. The severely truncated receptors were retained in the ER and failed to bind ligands. If overexpressed, even a substantial portion of the full-length receptor was retained in the ER in a form that was not functional. These data indicate that folding is rate limiting in export from the ER and that the proximal segment of the carboxyl terminus provides a docking site for the machinery involved in folding and quality control. In addition, the proximal portion is also important in G protein coupling. This latter role was unmasked when the distal portion of the C-tail (the extreme 18 amino acids, including a palmitoylated cysteine) had been removed; the resulting receptor was functional and transferred the agonist-mediated signal more efficiently than the full-length receptor. Signaling was enhanced because the coupling affinity increased (by 3-fold), which translated into a higher agonist potency. Thus, the distal portion of the carboxyl terminus provides for an autoinhibitory restraint, presumably by folding back and preventing G protein access to the proximal part of the C-tail.
Received for publication, December 18, 2002 , and in revised form, May 19, 2003.
* This work was supported by Austrian Science Foundation/FWF Grants 14273 and 16083, European Commission Grant QLTG3-CT-2001-00929, and the Oesterreichischer Austauschdienst (OEAD; Austrian Student Exchange Service). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 43-1-4277-64175; Fax:
43-1-4277-9641; E-mail:
christian.nanoff{at}univie.ac.at.
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