What we can learn from fish calcitonin and its receptor: Evolutionary insights and medical potential

A correspondence was published in LabMed Discovery (Volume 2, Issue 4, December 2025, 100108) introducing the novel ideas of overcoming the long-standing clinical challenge of calcitonin tachyphylaxis, offering innovative therapeutic directions by unraveling the evolutionary and molecular differences between fish and human calcitonin (CT)-calcitonin receptor (CTR) systems. Led by Professor Jian-min Liu from Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, the paper bridges evolutionary biology, structural biology, and translational medicine, providing a fresh framework for developing long-acting calcitonin therapies.

Calcitonin, a 32-amino-acid hormone secreted by thyroid C-cells, plays a crucial role in calcium homeostasis by inhibiting osteoclast-mediated bone resorption and promoting renal calcium excretion. However, the clinical utility calcitonin is severely limited by rapid receptor desensitization—within days of administration, the drug’s efficacy diminishes significantly, hampering long-term treatment of conditions such as osteoporosis, Paget’s disease, and hypercalcemia.

In contrast, marine teleosts have evolved a unique CT-CTR system that resists desensitization, enabling lifelong calcium regulation in high-calcium seawater environments (10–10.5 mmol/L) to avoid lethal hypercalcemia. The research team systematically reviewed the structural divergences between fish and human CT-CTR systems, uncovering key mechanisms underlying this evolutionary adaptation.

At the receptor structural level: Fish calcitonin receptors (CTRs) possess a unique multi-hormone binding domain (HBD). Their N-terminal extracellular domain contains an extended loop region and clusters of hydrophobic residues (e.g., additional disulfide bonds and glycosylation sites) that enhance high-affinity binding to salmon CT (sCT) through optimized hydrophobic packing and hydrogen-bond networks. With extremely low dependence on receptor activity-modifying proteins (RAMPs), fish CTRs can independently achieve high-affinity ligand binding. In contrast, human CTRs require heterodimerization with RAMPs to form functional receptors. This binding remodels the CTR structure, accelerates β-arrestin-mediated receptor internalization, and ultimately leads to receptor desensitization.

At the ligand structural level: Salmon calcitonin (sCT) shares only 50% sequence homology with human calcitonin (hCT). sCT can form a stable α-helical structure (residues 8–22), which deeply inserts into the transmembrane core of the receptor with a dissociation half-life of up to 13.2 hours. By comparison, the helical structure formed by hCT is unstable and completely dissociates within 4 hours, resulting in rapid signal termination.

Building on these insights, the study proposes two actionable translational strategies. First, design sCT analogs that mimic the stable α-helical structure of fish calcitonin to enhance ligand-receptor binding stability. Second, develop RAMP-independent CTR agonists or allosteric modulators to bypass the β-arrestin-mediated desensitization pathway. These strategies provide a clear blueprint for the development of long-acting calcitonin drugs.

About the Research Team

The study was led by Professor Jian-min Liu, MD, PhD, from the Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.

Citation

Yang Y, Liu J. What we can learn from fish calcitonin and its receptor: evolutionary insights and medical potential. LabMed Discovery 2025;2:100108. doi: 10.1016/j.lmd.2025.100108.