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Vol. 55, Issue 6, 1054-1059, June 1999
Receptor Systems, Molecular Pharmacology Unit, GlaxoWellcome
Research and Development, Medicines Research Centre, Hertfordshire,
United Kingdom
The calcitonin receptor-like receptor (CRLR) can function as either a
receptor for calcitonin gene-related peptide (CGRP) or for
adrenomedullin (ADM), depending upon the coexpression of a novel family
of single transmembrane proteins, which we have called receptor
activity modifying proteins or RAMPs. RAMPs 1, 2, and 3 transport CRLR
to the plasma membrane with similar efficiencies, however RAMP1
presents CRLR as a terminally glycosylated, mature glycoprotein and a
CGRP receptor, whereas RAMPs 2 and 3 present CRLR as an immature, core
glycosylated ADM receptor. Characterization of the RAMP2/CRLR and
RAMP3/CRLR receptors in HEK293T cells by radioligand binding
(125I-ADM as radioligand), functional assay (cAMP
measurement), or biochemical analysis (SDS-polyacrylamide gel
electrophoresis) revealed them to be indistinguishable, even though
RAMPs 2 and 3 share only 30% identity. Chimeric proteins were created
with the transmembrane and cytosolic portions of RAMP1 associated with the amino terminus of RAMP2 (RAMP2/1) and vice versa (RAMP1/2). Coexpression of RAMP2/1 with CRLR formed a core glycosylated ADM receptor, whereas the RAMP1/2 chimera generated both core glycosylated and mature forms of CRLR and enabled both ADM and CGRP receptor binding. Hence, the glycosylation state of CRLR appears to correlate with its pharmacology.
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