Receptor activity-modifying proteins 2 and 3 have distinct physiological functions from embryogenesis to old age.
RAMPs (receptor activity modifying proteins) impart remarkable effects on G protein-coupled receptor (GPCR) signaling. First identified through an interaction with the calcitonin receptor-like receptor (CLR), these single transmembrane proteins are now known to modulate the in vitro ligand binding affinity, trafficking, and second messenger pathways of numerous GPCRs. Consequently, the receptor-RAMP interface represents an attractive pharmacological target for the treatment of disease. Although the three known mammalian RAMPs differ in their sequences and tissue expression, results from in vitro biochemical and pharmacological studies suggest that they have overlapping effects on the GPCRs with which they interact. Therefore, to determine whether RAMP2 and RAMP3 have distinct functions in vivo, we generated mice with targeted deletions of either the RAMP2 or RAMP3 gene. Strikingly, we found that, although RAMP2 is required for survival, mice that lack RAMP3 appear normal until old age, at which point they have decreased weight. In addition, mice with reduced expression of RAMP2 (but not RAMP3) display remarkable subfertility. Thus, each gene has functions in vivo that cannot be accomplished by the other. Because RAMP2, RAMP3, and CLR transduce the signaling of the two potent vasodilators adrenomedullin and calcitonin gene-related peptide, we tested the effects of our genetic modifications on blood pressure, and no effects were detected. Nevertheless, our studies reveal that RAMP2 and RAMP3 have distinct physiological functions throughout embryogenesis, adulthood, and old age, and the mice we have generated provide novel genetic tools to further explore the utility of the receptor-RAMP interface as a pharmacological target.
Dackor
Ryan
R
Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599; Genetics Department, University of North Carolina, Chapel Hill, North Carolina 27599.
Fritz-Six
Kim
K
Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599; Genetics Department, University of North Carolina, Chapel Hill, North Carolina 27599.
Smithies
Oliver
O
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599.
Caron
Kathleen
K
Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599; Genetics Department, University of North Carolina, Chapel Hill, North Carolina 27599. Electronic address: Kathleen_caron@med.unc.edu.
D053607:Adrenomedullin / Q000378:metabolism; D000375:Aging; D000818:Animals; D001794:Blood Pressure; D015740:Calcitonin Gene-Related Peptide / Q000737:chemistry; D058286:Calcitonin Receptor-Like Protein; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006339:Heart Rate; D006579:Heterozygote; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008024:Ligands; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D011485:Protein Binding; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin / Q000378:metabolism
D058286:Calcitonin Receptor-Like Protein; C545579:Calcrl protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; C545506:Ramp2 protein, mouse; C545507:Ramp3 protein, mouse; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide