Abstract
When coexpressed with receptor activity-modifying protein (RAMP)2 or -3, calcitonin receptor-like receptor (CRLR) functions as an adrenomedullin (AM) receptor (CRLR/RAMP2 or -3). Coexpression of rat (r)CRLR with rRAMP deletion mutants in HEK293T cells revealed that deletion of residues 93-99 from rRAMP2 or residues 58-64 from rRAMP3 significantly inhibits high-affinity [125I]AM binding and AM-evoked cAMP production, despite full cell surface expression of the receptor heterodimer. Apparently, these two seven-residue segments are key determinants of high-affinity agonist binding to rAM receptors and of receptor functionality. Consequently, their deletion yields peptides that are able to serve as negative regulators of AM receptor function.
MeSH terms
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Adrenomedullin
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Animals
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Binding, Competitive / physiology
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Calcitonin Receptor-Like Protein
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Cyclic AMP / biosynthesis
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Dimerization
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Flow Cytometry
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Humans
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Peptides / metabolism*
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Protein Binding / physiology
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Protein Structure, Tertiary / physiology
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Radioligand Assay
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Rats
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Receptor Activity-Modifying Protein 2
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Receptor Activity-Modifying Proteins
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Receptors, Calcitonin / genetics
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Receptors, Calcitonin / metabolism*
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Sequence Alignment
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Sequence Deletion
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Sequence Homology, Amino Acid
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Structure-Activity Relationship
Substances
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CALCRL protein, human
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Calcitonin Receptor-Like Protein
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Calcrl protein, mouse
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Calcrl protein, rat
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Peptides
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RAMP2 protein, human
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Ramp2 protein, mouse
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Ramp2 protein, rat
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Receptor Activity-Modifying Protein 2
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Receptor Activity-Modifying Proteins
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Receptors, Calcitonin
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Adrenomedullin
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Cyclic AMP