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Single-Cell Calcium Imaging for Studying the Activation of Calcium Ion Channels
Published on: December 13, 2024
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Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor
Tianlei Wen1, Ziyu Wang1, Xiaozhe Chen1
1State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300350, China.
Science Advances
|June 5, 2021
Summary
Structural insights into the calcium-sensing receptor (CaSR) reveal how ligands activate this class C GPCR. These findings provide a framework for understanding CaSR modulation and developing therapies for endocrine disorders.
Area of Science:
- Biochemistry
- Structural Biology
- Endocrinology
Background:
- The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor crucial for calcium homeostasis and parathyroid hormone regulation.
- Understanding CaSR's structure is vital for developing treatments for related endocrine disorders.
Purpose of the Study:
- To elucidate the structural mechanisms underlying CaSR activation and allosteric modulation.
- To map disease-causing mutations onto the CaSR structure for therapeutic insights.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine the structures of full-length CaSR in various ligand-bound states.
- Analysis of ligand binding sites and conformational changes within the extracellular and transmembrane domains.
Main Results:
- Multiple cryo-EM structures revealed CaSR activation through ligand binding (Ca2+, l-tryptophan) to the extracellular domain, inducing conformational changes.
- Positive (evocalcet) and negative (NPS-2143) allosteric modulators bind to a common pocket in the transmembrane domain, with NPS-2143 inducing an inactive conformation.
- Mapping of 305 disease-associated mutations identified hotspots for five clinical endocrine disorders.
Conclusions:
- The study provides a structural framework for CaSR activation and allosteric modulation by small molecules.
- These structural insights can guide the development of novel therapeutic strategies for CaSR-related diseases.
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