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Vol. 56, Issue 1, 235-242, July 1999
Molecular Pharmacology Laboratory, Department of Pharmacology, The
University of Melbourne, Victoria, Australia (G.C., K.J.P., M.M., N.T.,
Y.G., P.M.S.); and Receptor Systems Unit, Glaxo Wellcome Medicines
Research Centre, Stevenage, Hertfordshire United Kingdom (N.J.F.,
M.J.M., S.M.F.)
Receptor activity-modifying proteins (RAMPs) are single-transmembrane
proteins that transport the calcitonin receptor-like receptor (CRLR) to
the cell surface. RAMP 1-transported CRLR is a calcitonin gene-related
peptide (CGRP) receptor. RAMP 2- or RAMP 3-transported CRLR is an
adrenomedullin receptor. The role of RAMPs beyond their interaction
with CRLR, a class II G protein-coupled receptor, is unclear. In this
study, we have examined the role of RAMPs in generating amylin receptor
phenotypes from the calcitonin (CT) receptor gene product.
Cotransfection of RAMP 1 or RAMP 3 with the human CT receptor lacking
the 16-amino acid insert in intracellular domain 1 (hCTRI1
) into COS-7 cells induced specific
125I-labeled rat amylin binding. RAMP 2 or vector
cotransfection did not cause significant increases in specific amylin
binding. Competition-binding characterization of the RAMP-induced
amylin receptors revealed two distinct phenotypes. The RAMP 1-derived amylin receptor demonstrated the highest affinity for salmon CT (IC50, 3.01 ± 1.44 × 1010 M), a
high to moderate affinity for rat amylin (IC50, 7.86 ± 4.49 × 109 M) and human CGRP
(IC50, 2.09 ± 1.63 × 108 M), and
a low affinity for human CT (IC50, 4.47 ± 0.78 × 107 M). In contrast, whereas affinities for amylin and
the CTs were similar for the RAMP 3-derived receptor, the efficacy of
human CGRP was markedly reduced (IC50, 1.12 ± 0.45 × 107 M; P < .05 versus
RAMP 1). Functional cyclic AMP responses in COS-7 cells cotransfected
with individual RAMPs and hCTRI1 were reflective of the
phenotypes seen in competition for amylin binding. Confocal microscopic
localization of c-myc-tagged RAMP 1 indicated that, when transfected
alone, RAMP 1 almost exclusively was located intracellularly.
Cotransfection with calcitonin receptor (CTR)I1 induced
cell surface expression of RAMP 1. The results of experiments
cross-linking 125I-labeled amylin to RAMP
1/hCTR-transfected cells with bis succidimidyl suberate were suggestive
of a cell-surface association of RAMP 1 and the receptors. Our
data suggest that in the CT family of receptors, and potentially in
other class II G protein-coupled receptors, the cellular phenotype is
likely to be dynamic in regard to the level and combination of both the
receptor and the RAMP proteins.
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