RAMPs are an unusual class of GPCR accessory proteins that chaperone receptors to the cell surface and impart allosteric regulation of ligand binding specificity, functional selectivity and intracellular trafficking of a variety of GPCRs. RAMPs, first identified in the context of the adrenomedullin receptor, represent a unique paradigm for GPCR functional regulation which is currently being exploited by the pharmaceutical industry. Our laboratory was the first to generate and characterize genetic mouse models null for each of the 3 Ramp genes. Phenotypic characterization of these models has permitted us to functionally validate the requirement and roles of RAMPs for controlling the signaling of many family B GPCR ligands, including adrenomedullin, CGRP, VIP and CRF. Most importantly, we have been able to use these genetic tools and in vitro biochemistry and pharmacology approaches to expand the current repertoire of RAMP-interacting GPCRs, thereby providing novel pharmacological targets for the modulation of a wide variety of pathophysiological conditions including skeletal wasting, hypothalamic-pituitary imbalance, asthma and cardiac failure. Our current studies are geared towards characterizing the pharmacological and physiological roles of RAMPs with several newly identified partners in the chemokine/cytokine GPCR subfamily.
- Kadmiel M, Fritz-Six K, Pacharne S, Richards G, Skerry T and Caron KM Haploinsufficiency of receptor activity modifying protein 2 (Ramp2) causes reduced fertility, hyperprolactinemia, skeletal abnormalities and endocrine dysfunction in mice. Molecular Endocrinology 2011 Jul; 25(7):1244-53.
- Lenhart PM, Broselid S, Barrick CJ, Leeb-Lundberg LM, Caron KM G-protein-coupled receptor 30 interacts with receptor activity-modifying protein 3 and confers sex-dependent cardioprotection. J Mol Endocrinol. 2013 Jul; 51(1):191-202.
- Li M, Wetzel-Strong SE, Hua X, Tilley SL, Oswald E, Krummel MF, Caron KM. Deficiency of RAMP1 attenuates antigen-induced airway hyperresponsiveness in mice. PLoS One. 2014 Jul; 9(7):e102356
- Klein KR, Karpinich NO, Espenschied ST, Willcockson HH, Dunworth WP, Hoopes SL, Kushner EJ, Bautch VL, Caron KM 2014 Decoy Receptor CXCR7 Modulates Adrenomedullin-Mediated Cardiac and Lymphatic Vascular Development. Developmental Cell. 2014 Sept; 30(5):528-40
- Kechele DO, Dunworth WP, Trincot CE, Wetzel-Strong SE, Li M, Ma H, Liu J, Caron KM. Endothelial Restoration of Receptor Activity–Modifying Protein 2 Is Sufficient to Rescue Lethality, but Survivors Develop Dilated Cardiomyopathy Hypertension. 2016 Sep; 68(3):667-77
- Klein KR, Matson BC and Caron KM. The expanding repertoire of receptor activity modifying protein (RAMP) function. Critical Reviews in Biochemistry & Molecular Biology. 2016; 51(1):65-71.