Ramp1, short for receptor activity-modifying protein 1, is a key component of the G protein-coupled receptor adapter family. It functions as the receptor for the neuropeptide calcitonin gene-related peptide (CGRP), playing a crucial role in multiple physiological and pathological processes. The CGRP-Ramp1 axis is involved in various biological pathways, including those related to neuro-epithelial crosstalk, neuro-immune communication, and cell-cell signaling, highlighting its overall biological importance. Genetic models, such as knockout (KO) mouse models, have been instrumental in studying its functions.

In KO mouse models, the absence of Ramp1 has shown diverse impacts. In the gut, nociceptor-goblet cell communication via the CGRP-Ramp1 axis is disrupted, leading to decreased mucus thickness, dysbiosis, increased epithelial stress, and susceptibility to colitis [1]. In endometriosis, nociceptor-macrophage communication through CGRP-Ramp1 signaling drives pain and lesion growth, and blocking this axis reduces these symptoms [2]. In the skin, the CGRP-Ramp1 axis in commensal-specific T cells modulates cutaneous adaptive immunity to the microbiota [3]. In the liver, RAMP1-KO mice have exacerbated ischemia-reperfusion injury due to increased activation of the ERK/YAP pathway [4]. In melanoma, antagonizing the CGRP receptor RAMP1 reduces the exhaustion of tumour-infiltrating leukocytes and tumour growth [5]. In wound repair and muscle regeneration, ablation of the NaV1.8 nociceptor (which signals through CGRP-Ramp1) impairs these processes [6]. In gastric cancer, disrupting the CGRP/Ramp1 axis between nociceptive neurons and cancer cells suppresses tumour growth [7]. In acute lung injury, RAMP1-deficient mice have higher lung injury scores and cytokine levels [8]. In inflammation-associated lymphangiogenesis, RAMP1-deficient mice show suppressed lymphangiogenesis [9].

In conclusion, Ramp1, through the CGRP-Ramp1 axis, is essential for maintaining normal physiological functions in multiple tissues and organs. Studies using KO mouse models have revealed its significance in various disease conditions, including gut-related diseases, endometriosis, skin immunity, liver injury, cancer, wound repair, and lung injury. These findings provide potential therapeutic targets for treating these diseases by modulating the CGRP-Ramp1 axis.

References:

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2. Fattori, Victor, Zaninelli, Tiago H, Rasquel-Oliveira, Fernanda S, Verri, Waldiceu A, Rogers, Michael S. 2024. Nociceptor-to-macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice. In Science translational medicine, 16, eadk8230. doi:10.1126/scitranslmed.adk8230. https://pubmed.ncbi.nlm.nih.gov/39504351/

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5. Balood, Mohammad, Ahmadi, Maryam, Eichwald, Tuany, Woolf, Clifford J, Talbot, Sebastien. 2022. Nociceptor neurons affect cancer immunosurveillance. In Nature, 611, 405-412. doi:10.1038/s41586-022-05374-w. https://pubmed.ncbi.nlm.nih.gov/36323780/

6. Lu, Yen-Zhen, Nayer, Bhavana, Singh, Shailendra Kumar, Akira, Shizuo, Martino, Mikaël M. 2024. CGRP sensory neurons promote tissue healing via neutrophils and macrophages. In Nature, 628, 604-611. doi:10.1038/s41586-024-07237-y. https://pubmed.ncbi.nlm.nih.gov/38538784/

7. Zhi, Xiaofei, Wu, Feijing, Qian, Jin, Ryeom, Sandra W, Wang, Timothy C. 2024. Nociceptive neurons interact directly with gastric cancer cells via a CGRP/Ramp1 axis to promote tumor progression. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.03.04.583209. https://pubmed.ncbi.nlm.nih.gov/38496544/

8. Yamashita, Atsushi, Ito, Yoshiya, Osada, Mayuko, Okamoto, Hirotsugu, Amano, Hideki. 2024. RAMP1 Signaling Mitigates Acute Lung Injury by Distinctively Regulating Alveolar and Monocyte-Derived Macrophages. In International journal of molecular sciences, 25, . doi:10.3390/ijms251810107. https://pubmed.ncbi.nlm.nih.gov/39337592/

9. Tsuru, Seri, Ito, Yoshiya, Matsuda, Hiromi, Okamoto, Hirotsugu, Majima, Masataka. 2020. RAMP1 signaling in immune cells regulates inflammation-associated lymphangiogenesis. In Laboratory investigation; a journal of technical methods and pathology, 100, 738-750. doi:10.1038/s41374-019-0364-0. https://pubmed.ncbi.nlm.nih.gov/31911634/