Recent advances in calcium-sensing receptor structures and signaling pathways

Area of Science:

• Biochemistry and Molecular Biology
• Endocrinology
• Structural Biology

Background:

• The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) essential for maintaining extracellular calcium homeostasis.
• CaSR regulates parathyroid hormone release and urinary calcium excretion, critical for calcium balance.
• Germline mutations in CaSR lead to disorders of calcium homeostasis, highlighting its physiological importance.

Purpose of the Study:

• To elucidate the structural mechanisms underlying CaSR activation and allosteric modulation.
• To understand how CaSR interacts with other proteins to achieve rapid and diverse physiological responses.
• To integrate recent structural and functional findings to advance the understanding of CaSR signaling.

Main Methods:

• Analysis of five recent cryo-electron microscopy (cryo-EM) structures of the near full-length CaSR.
• Investigation of functional effects of germline CaSR mutations.
• Identification and characterization of CaSR interacting proteins.

Main Results:

• Cryo-EM structures reveal how agonist binding transmits signals from the extracellular domain to the transmembrane region for G protein activation.
• Structural dynamics influenced by allosteric modulators have been elucidated.
• Recent studies identified novel CaSR interacting proteins that regulate its signaling and trafficking.

Conclusions:

• Recent structural breakthroughs provide unprecedented insights into CaSR activation mechanisms.
• Understanding CaSR-protein interactions is key to deciphering its complex physiological roles.
• These findings advance the study of calcium homeostasis and CaSR-targeted therapeutics.