Adrenomedullin 2 receptor (AM2 receptor) (AM2 receptor)

The Adrenomedullin 2 receptor (AM2 receptor) is a heteromeric protein complex formed by the association of the Calcitonin receptor-like receptor (CLR), a Class B G protein-coupled receptor, and the Receptor activity-modifying protein 3 (RAMP3) [1, 18]. This complex functions as a high-affinity receptor for the peptide hormones adrenomedullin and adrenomedullin 2 (intermedin), playing a critical role in cardiovascular and lymphatic homeostasis [4, 10]. Upon ligand binding, the receptor activates Gs-mediated signaling, leading to increased cAMP production and subsequent vasodilation, angiogenesis, and regulation of fluid balance [19]. In pathological contexts, particularly oncology, the AM2 receptor is frequently overexpressed and contributes to tumor progression by promoting cell proliferation, survival, and metastasis [1, 2]. It is also implicated in cardiovascular diseases, sepsis, and preeclampsia, where dysregulated adrenomedullin signaling affects vascular tone and integrity [12, 15]. Therapeutic strategies targeting this complex include the development of selective small-molecule antagonists to inhibit pro-tumoral pathways while avoiding the systemic hypotension associated with broader adrenomedullin inhibition [2, 12]. Conversely, agonists are explored for their potential cardioprotective and vasodilatory benefits in heart failure and hypertension [17, 19].

Other names

Calcitonin receptor-like receptor / RAMP3 complexCLR/RAMP3 complexAM2RAdrenomedullin receptor 2Calcitonin receptor-like receptor / Receptor activity-modifying protein 3 complex

The AM2 receptor primarily signals through the Gs-adenylyl cyclase pathway, where agonist binding (e.g., adrenomedullin) triggers the production of cAMP, leading to vasodilation and cardioprotective effects [19]. In cancer, the receptor promotes tumor growth and angiogenesis; thus, antagonism of the CLR/RAMP3 complex inhibits these pro-tumoral signals by blocking downstream pathways such as ERK/MAPK and PI3K/Akt [1, 2].