Adrenomedullin receptor 1 (AM1) (AM1)

The Adrenomedullin receptor 1 (AM1) is a heterodimeric G protein-coupled receptor (GPCR) complex formed by the association of the Calcitonin receptor-like receptor (CLR) and the Receptor activity-modifying protein 2 (RAMP2) (PMID: 10333551). It serves as the primary high-affinity receptor for the peptide hormone adrenomedullin, a potent endogenous vasodilator and regulator of endothelial integrity (UniProt: Q16602). In the cardiovascular system, AM1 signaling through the Gs-cAMP pathway promotes vascular relaxation and stabilizes the endothelial barrier, which is crucial for maintaining blood pressure and preventing edema (PMID: 29466702). Dysregulation of the AM1 pathway is implicated in various pathologies, including septic shock, where excessive adrenomedullin leads to hypotension, and heart failure, where it acts as a compensatory mechanism (PMID: 30135318). In oncology, AM1 is often exploited by tumors to drive angiogenesis and lymphangiogenesis, facilitating growth and metastasis (PMID: 19129245). Therapeutic interventions include the use of monoclonal antibodies like Adrecizumab to modulate ligand availability or small molecule antagonists to inhibit tumor-associated signaling (ClinicalTrials.gov: NCT03085758).

Other names

CLR/RAMP2 complexCalcitonin receptor-like receptor/Receptor activity-modifying protein 2 complexAdrenomedullin 1 receptorCALCRL/RAMP2

Activation of the AM1 receptor complex by adrenomedullin triggers Gs protein coupling, which stimulates adenylate cyclase to increase intracellular cAMP. This signaling cascade leads to protein kinase A (PKA) activation, resulting in the relaxation of vascular smooth muscle cells and the stabilization of endothelial cell-cell junctions through the regulation of the cytoskeleton and adhesion molecules.