Structure and function of the human calcium-sensing receptor: Insights from natural and engineered mutations and allosteric modulators: Ca2+-Sensing Receptor Review Series

Introduction The CaR is a unique family 3 GPCR Architecture of the CaR Venus flytrap domain Cysteine-rich domain Seven-transmembrane domain Intracellular carboxyl terminus Naturally occurring inactivating mutations associated with FHH and NSHPT Naturally occurring activating mutations associated with ADH and Bartter's syndrome type V Allosteric modulators of the CaR and their therapeutic potentials Positive allosteric modulators Negative allosteric modulators Concluding remarks The human extracellular Ca ²⁺-sensing receptor (CaR), a member of the G protein-coupled receptor family 3, plays a key role in the regulation of extracellular calcium homeostasis. It is one of just a few G protein-coupled receptors with a large number of naturally occurring mutations identified in patients. In contrast to the small sizes of its agonists, this large dimeric receptor consists of domains with topologically distinctive orthos-teric and allosteric sites. Information derived from studies of naturally occurring mutations, engineered mutations, allosteric modulators and crystal structures of the agonist-binding domain of homologous type 1 metabotropic glutamate receptor and G protein-coupled rhodopsin offers new insights into the structure and function of the CaR.