The Calcium-Sensing Receptor (CaSR) in Disease

Calcium (Ca²⁺) is fundamental to organic life, and the ability to detect and respond to changes in extracellular Ca²⁺ ions (Ca²⁺_o) is paramount to all living organisms. The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) that senses minute fluctuations in Ca²⁺_o. In higher order vertebrates, the CaSR’s best characterized function is maintenance of serum Ca²⁺_o concentrations via inhibitory regulation of parathyroid hormone (PTH) secretion from the parathyroid glands, control of renal ion and salt excretion, stimulation of calcitonin secretion from the thyroid gland, and regulation of osteoblast and osteoclast activity in the bone. However, the CaSR is essential for additional fundamental biological processes, including neurotransmission, inflammation, macropinocytosis, release of gut hormones and macronutrient digestion, vascular tone and blood pressure, lung function, and the development and maintenance of various organs via effects on cell fate [1]. CaSR achieves these diverse functions by responding not only to Ca²⁺_o but also to numerous endogenous stimuli, such as di- and tri-valent cations, l-amino acids, gamma;-glutamyl peptides, polyamines, polycationic peptides, and changes in pH. Hence, despite the name, the CaSR is a multimodal chemosensor. Unlike most receptors that serve multiple functions through alternative subtypes or splice variants, the CaSR’s divergent roles in different tissues are likely achieved through its multiliganded activity. This chapter examines CaSR biochemistry, its role in human (patho)physiology and its potential as a therapeutic target.