The Calcium-Sensing Receptor: A Molecular Perspective

Since the discovery of the calcium-sensing receptor, studies reveal that it can detect not only calcium but a host of extracellular signals and that besides its key role in calcium homeostasis the receptor is involved in a myriad of unrelated biological processes. This review provides a comprehensive exploration of the receptor, including its structure, stimuli, signaling pathways, interacting protein partners and tissue expression patterns, and relates the impact of these different aspects of the calcium-sensing receptor to its functionality from a molecular perspective. Compelling evidence of a cell surface receptor sensitive to extracellular calcium was observed as early as the 1980s and was finally realized in 1993 when the calcium-sensing receptor (CaR) was cloned from bovine parathyroid tissue. Initial studies relating to the CaR focused on its key role in extracellular calcium homeostasis, but as the amount of information about the receptor grew it became evident that it was involved in many biological processes unrelated to calcium homeostasis. The CaR responds to a diverse array of stimuli extending well beyond that merely of calcium, and these stimuli can lead to the initiation of a wide variety of intracellular signaling pathways that in turn are able to regulate a diverse range of biological processes. It has been through the examination of the molecular characteristics of the CaR that we now have an understanding of how this single receptor is able to convert extracellular messages into specific cellular responses. Recent CaR-related reviews have focused on specific aspects of the receptor, generally in the context of the CaR's role in physiology and pathophysiology. This review will provide a comprehensive exploration of the different aspects of the receptor, including its structure, stimuli, signalling, interacting protein partners, and tissue expression patterns, and will relate their impact on the functionality of the CaR from a molecular perspective.