Adrenomedullin receptor 2 (AM2) (AM2)

The Adrenomedullin receptor 2 (AM2) is a heterodimeric G protein-coupled receptor formed by the association of the Calcitonin receptor-like receptor (CALCRL) and the Receptor activity-modifying protein 3 (RAMP3) [1, 2]. It serves as a primary mediator for the biological actions of adrenomedullin, a peptide hormone involved in the regulation of vascular tone and endothelial integrity [3]. Activation of the AM2 receptor triggers the Gs-adenylyl cyclase-cAMP signaling pathway, leading to potent vasodilation and the stabilization of the blood-brain and blood-lymph barriers [4, 5]. In addition to its cardiovascular roles, AM2 is essential for proper lymphatic vascular development and fluid homeostasis [4]. Pathologically, the receptor is implicated in the progression of various cancers, where it promotes tumor-associated angiogenesis and lymphangiogenesis [6]. It also plays a significant role in the inflammatory response, particularly in sepsis, where its modulation can influence capillary leak and organ failure [5]. Therapeutic interest in AM2 focuses on agonists for treating heart failure and hypertension, as well as antagonists or neutralizing antibodies to inhibit tumor growth and metastasis [7]. Clinical monitoring of this pathway often utilizes mid-regional pro-adrenomedullin (MR-proADM) as a biomarker for disease severity and treatment efficacy [5].

Other names

AM2 receptorCALCRL/RAMP3 complexCalcitonin receptor-like receptor/Receptor activity-modifying protein 3 complexAdrenomedullin 2 receptor

The Adrenomedullin receptor 2 functions through the activation of Gs proteins upon ligand binding, which stimulates adenylyl cyclase to increase intracellular cyclic AMP (cAMP) levels [1, 2]. This signaling cascade activates protein kinase A (PKA) and the PI3K/Akt pathway, leading to the phosphorylation of endothelial nitric oxide synthase (eNOS), resulting in nitric oxide production and vasodilation [3, 7]. Additionally, AM2 signaling stabilizes the endothelial cytoskeleton, thereby enhancing vascular barrier function and reducing capillary leak in inflammatory conditions [5].