Linked Life Data

11847213

Source:http://linkedlifedata.com/resource/pubmed/id/11847213

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
16
pubmed:dateCreated
2002-4-15
pubmed:databankReference
pubmed:abstractText
The heterodimeric CGRP receptor requires co-expression of calcitonin receptor-like receptor (CRLR) and an accessory protein called receptor activity-modifying protein (RAMP) 1 (McLatchie, L. M., Fraser, N. J., Main, M. J., Wise, A., Brown, J., Thompson, N., Solari, R., Lee, M. G., and Foord, S. M. (1998) Nature 393, 333-339). Several non-peptide CGRP receptor antagonists have been shown to exhibit marked species selectivity, with >100-fold higher affinities for the human CGRP receptor than for receptors from other species (Doods, H., Hallermayer, G., Wu, D., Entzeroth, M., Rudolf, K., Engel, W., and Eberlein, W. (2000) Br. J. Pharmacol. 129, 420-423; Edvinsson, L., Sams, A., Jansen-Olesen, I., Tajti, J., Kane, S. A., Rutledge, R. Z., Koblan, K. S., Hill, R. G., and Longmore, J. (2001) Eur. J. Pharmacol. 415, 39-44). This observation provided an opportunity to map the determinants of receptor affinity exhibited by BIBN4096BS and the truncated analogs, Compounds 1 and 2. All three compounds exhibited higher affinity for the human receptor, human CRLR/human RAMP1, than for the rat receptor, rat CRLR/rat RAMP1. We have now demonstrated that this species selectivity was directed exclusively by RAMP1. By generating recombinant human/rat CRLR/RAMP1 receptors, we demonstrated that co-expression of human CRLR with rat RAMP1 produced rat receptor pharmacology, and vice versa. Moreover, with rat/human RAMP1 chimeras and site-directed mutants, we have identified a single amino acid at position 74 of RAMP1 that modulates the affinity of small molecule antagonists for CRLR/RAMP1. Replacement of lysine 74 in rat RAMP1 with tryptophan (the homologous amino acid in the human receptor) resulted in a > or =100-fold increase in antagonist affinities, similar to the K(i) values for the human receptor. These observations suggest that important determinants of small molecule antagonist affinity for the CGRP receptor reside within the extracellular region of RAMP1 and provide evidence that this receptor accessory protein may participate in antagonist binding.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
19
pubmed:volume
277
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
14294-8
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:11847213-Amino Acid Sequence, pubmed-meshheading:11847213-Animals, pubmed-meshheading:11847213-Binding, Competitive, pubmed-meshheading:11847213-Blotting, Western, pubmed-meshheading:11847213-Brain, pubmed-meshheading:11847213-Cell Membrane, pubmed-meshheading:11847213-Cloning, Molecular, pubmed-meshheading:11847213-DNA, Complementary, pubmed-meshheading:11847213-Humans, pubmed-meshheading:11847213-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:11847213-Kinetics, pubmed-meshheading:11847213-Ligands, pubmed-meshheading:11847213-Membrane Proteins, pubmed-meshheading:11847213-Models, Chemical, pubmed-meshheading:11847213-Molecular Sequence Data, pubmed-meshheading:11847213-Protein Binding, pubmed-meshheading:11847213-Rats, pubmed-meshheading:11847213-Receptor Activity-Modifying Protein 1, pubmed-meshheading:11847213-Receptor Activity-Modifying Proteins, pubmed-meshheading:11847213-Recombinant Fusion Proteins, pubmed-meshheading:11847213-Transfection
pubmed:year
2002
pubmed:articleTitle
Receptor activity-modifying protein 1 determines the species selectivity of non-peptide CGRP receptor antagonists.
pubmed:affiliation
Molecular Pharmacology Department, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
pubmed:publicationType
Journal Article