Fish calcitonin receptor has novel features.

Area of Science:

• Endocrinology
• Molecular Biology
• Comparative Physiology

Background:

• Calcitonin (CT) isolated from fish has higher affinity to mammalian CT receptors (CTR) and is used to treat human bone diseases.
• The physiological roles of CT in fish and the characteristics of fish CTR remain largely unclarified.
• Understanding fish CTR is crucial for comparative endocrinology and potential therapeutic applications.

Purpose of the Study:

• To clone and characterize the calcitonin receptor (CTR) from mefugu (Takifugu obscurus).
• To elucidate the structure and pharmacological properties of fish CTR.
• To investigate the ligand-binding specificities and functional domains of fish CTR.

Main Methods:

• Cloning and full-length cDNA sequencing of mefugu CTR (mfCTR).
• Database mining to identify similar fish CTR structures.
• Pharmacological studies using various ligands (fish CT, CGRP, amylin) with mfRAMPs and deletion mutant analyses.

Main Results:

• Mefugu CTR (mfCTR) possesses four tandem N-terminal hormone-binding domains (HBDs), a feature common in some fish species.
• mfCTR binds fish CT, and also CGRP and amylin in combination with specific mfRAMPs (receptor activity-modifying proteins).
• mfCTR exhibits dual affinity sites and only the HBD nearest the transmembrane region is functional; human CT does not bind mfCTR.

Conclusions:

• Fish CTR represents the first example of a receptor with multiple HBD-like sequences.
• This study provides the first detailed characterization of the structure and properties of a fish CTR, revealing distinct ligand-binding capabilities.
• The findings highlight significant differences between fish and mammalian CTRs, impacting our understanding of calcium homeostasis regulation across species.