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Papers In Press, published online ahead of print September 21, 2004
Department of Pharmacology, University of Copenhagen, Copenhagen 2200
Corresponding Author: b.holst{at}molpharm.dk
Three members of the ghrelin receptor family were characterized in parallel: the ghrelin receptor, the neurotensin receptor 2 and the orphan receptor GPR39. All three receptors displayed a high degree of ligand-independent signalling activity. The constitutive activity of the ghrelin receptor and of NT-R2 through the Gq, phospholipase C pathway was approximately 50 % of their maximal capacity as determined through inositol phosphate accumulation. These two receptors also showed very high constitutive activity in activation of cAMP response element (CRE) driven transcription. GPR39 displayed a clear but lower degree of constitutive activity through the inositol phosphate and CRE pathways. In contrast GPR39 signalled with the highest constitutive activity in respect of activation of serum response element (SRE) dependent transcription conceivably partly through G12/13 and Rho kinase. Antibody feeding experiments demonstrated that the epitope-tagged ghrelin receptor was constitutively internalized but could be trapped at the cell surface by an inverse agonist, whereas GPR39 remained at the cell surface. Mutational analysis showed that the constitutive activity of both the ghrelin receptor and GPR39 could systematically be tuned up and down depending on the size and hydrophobicity of the side chain in position VI:16 in the context of an aromatic residue at VII:09 and a large hydrophobic residue at VII:06. It is concluded that the three ghrelin-like receptors display an unusually high degree of constitutive activity and that the structural basis for this is determined by an aromatic cluster on the inner face of the extracellular ends of TM-VI and –VII.
J. Biol. Chem, 10.1074/jbc.M407676200
Submitted on July 8, 2004
Revised on September 14, 2004
Accepted on September 21, 2004
Common structural basis for constitutive activity of the ghrelin receptor family
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