RAMP3, short for Receptor Activity-Modifying Protein 3, is an accessory protein that interacts with G-protein coupled receptors (GPCRs) [4]. It plays diverse roles in multiple biological processes. RAMP3 is involved in neuropeptide signalling, regulating T cell differentiation. It is also a component of the receptor for neuropeptide CGRP, where extracellular CGRP signalling through the RAMP3-CALCRL receptor restricts TH2 cell differentiation and promotes TH1 cell differentiation [1]. In addition, RAMP3 is related to the adrenomedullin system, which is crucial for maintaining cardiovascular homeostasis, energy metabolism, and anti-tumour functions [2,3,5].

In gene knockout mouse models, RAMP3-/-mice have shown significant phenotypes. In the context of cardiovascular stress, RAMP3-/-mice show reduced systolic function and enhanced fibrosis after transverse aortic constriction (TAC), with a reduction in cardiac lymphatic vessels being a characteristic feature, indicating its role in later adaptation to cardiovascular stress [2]. RAMP3-/-OVX mice exhibit greater obesity, higher serum insulin levels, and exacerbated hepatic steatosis, suggesting its role in energy metabolism and hepatoprotection in postmenopausal obesity [3]. In tumour-related studies, RAMP3-/-mice have suppressed tumour metastasis as the number of podoplanin-positive cancer-associated fibroblasts is reduced at metastatic sites [5].

In conclusion, RAMP3 is essential in regulating T cell differentiation, cardiovascular homeostasis, energy metabolism, and tumour-related processes. The study of RAMP3 knockout mouse models has significantly contributed to understanding its functions in these disease-associated biological processes, providing potential therapeutic targets for treating conditions such as postmenopausal obesity, cardiovascular diseases, and cancer metastasis.