Adrenomedullin 2 receptor (AM2R)

The Adrenomedullin 2 receptor (AM2R) is a heterodimeric G protein-coupled receptor complex formed by the association of the Calcitonin receptor-like receptor (CALCRL) and the Receptor activity-modifying protein 3 (RAMP3). Belonging to the Secretin-like (Class B) GPCR family, it is primarily activated by the endogenous peptide ligands adrenomedullin and adrenomedullin 2, the latter also known as intermedin. The AM2R plays a pivotal role in cardiovascular and lymphatic homeostasis by mediating potent vasodilation, regulating fluid balance, and facilitating lymphangiogenesis. A unique pharmacological feature of this receptor, conferred by the RAMP3 subunit, is its ability to recycle to the cell surface following internalization, which distinguishes its signaling profile from the closely related AM1 receptor. In disease states, the AM2R is frequently upregulated in various solid tumors, including pancreatic and breast cancers, where it promotes tumor proliferation and adapts the microenvironment to hypoxic conditions. Consequently, the receptor has emerged as a high-priority therapeutic target in oncology, with selective small-molecule antagonists being developed to inhibit tumor growth and metastasis without inducing the hypertensive side effects associated with broad adrenomedullin pathway blockade. Conversely, agonists of the AM2R signaling pathway are being investigated for therapeutic potential in treating heart failure and sepsis, aiming to stabilize the vascular endothelium and improve hemodynamic function. The receptor's involvement in both vascular stability and oncogenesis makes it a critical focus for drug discovery in cardiovascular and cancer medicine.

Other names

AM2 receptorAM2RIntermedin receptorCLR/RAMP3 complexCalcitonin receptor-like receptor/Receptor activity-modifying protein 3 complexCALCRL/RAMP3

The Adrenomedullin 2 receptor couples primarily to the Gs protein, leading to the activation of adenylate cyclase and an increase in intracellular cAMP levels, which mediates physiological responses such as vasodilation and anti-inflammatory effects. Therapeutic strategies include using selective antagonists to block pro-tumorigenic signaling in cancer or using agonists to promote vascular stability in cardiovascular and critical care settings.