Heterodimers and family-B GPCRs: RAMPs, CGRP and adrenomedullin.
RAMPs (receptor activity-modifying proteins) are single-pass transmembrane proteins that associate with certain family-B GPCRs (G-protein-coupled receptors). Specifically for the CT (calcitonin) receptor-like receptor and the CT receptor, this results in profound changes in ligand binding and receptor pharmacology, allowing the generation of six distinct receptors with preferences for CGRP (CT gene-related peptide), adrenomedullin, amylin and CT. There are three RAMPs: RAMP1-RAMP3. The N-terminus appears to be the main determinant of receptor pharmacology, whereas the transmembrane domain contributes to association of the RAMP with the GPCR. The N-terminus of all members of the RAMP family probably contains two disulphide bonds; a potential third disulphide is found in RAMP1 and RAMP3. The N-terminus appears to be in close proximity to the ligand and plays a key role in its binding, either directly or indirectly. BIBN4096BS, a CGRP antagonist, targets RAMP1 and this gives the compound very high selectivity for the human CGRP(1) receptor.
Conner
A C
AC
School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
Simms
J
J
Hay
D L
DL
Mahmoud
K
K
Howitt
S G
SG
Wheatley
M
M
Poyner
D R
DR
D053607:Adrenomedullin; D000595:Amino Acid Sequence; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000737:chemistry; D019281:Dimerization; D006031:Glycosylation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D058262:Receptor Activity-Modifying Protein 1; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin / Q000737:chemistry*; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000502:physiology*; D017386:Sequence Homology, Amino Acid
D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D010455:Peptides; C545502:RAMP1 protein, human; C545504:RAMP3 protein, human; D058262:Receptor Activity-Modifying Protein 1; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; D018015:Receptors, Calcitonin Gene-Related Peptide; D043562:Receptors, G-Protein-Coupled; D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide