title: Pharmacology of the calcium sensing receptor.
abstract: Calcium sensing receptor (CASR) is a G-protein couple receptor which plays a key role in calcium homeostasis in vertebrates. Its extracellular domain is sensitive to divalent cations, aminoacids and polyamines. In parathyroid glands, CASR activation causes parathyroid hormone (PTH) reduction and subsequently a decrease in blood calcium concentration. In PTH-dependent disorders, e.g. primary and secondary hyperparathyroidism (HPT), the need for therapeutic options other than surgery led to the synthesis of various allosteric CASR agonists (calcimimetics), such as cinacalcet. Cinacalcet is the only calcimimetic approved for HPT secondary to chronic kidney disease (CDK), parathyroid carcinoma, and, in some countries, primary HPT. Clinical trials showed that cinacalcet reduced PTH and calcemia both in CDK and primary HPT, lowering the risk of bone fractures, surgery, and cardiovascular complications in the former patients. Long-term safety and pharmacoeconomics have to be fully tested yet. Few both in vitro and in vivo studies showed an association between Arg990Gly-CASR polymorphism and cinacalcet sensitivity, though in patients with severe CASR inactivating mutations the drug substantially retained its positive clinical effects. Recently, a new class of allosteric antagonists of CASR, i.e. calcilytics, has been synthesized. Calcilytics are structurally similar to calcimimetics, but exert their effects acting on a different allosteric site. Infusion of calcilytics was followed by transient rise in PTH and calcium. One of these compounds, ronacaleret, was able to increase femur BMD in post menopausal women, but with induction of mild hyperparathyroidism. In the future, calcilytics may contribute to the osteoporosis treatment choice.
authors.affiliation: Endocrine and Diabetology Unit, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Filopanti
authors.affiliation: Department of Clinical and Community Sciences, University of Milan, Italy ; Endocrinology and Diabetology Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Corbetta
authors.affiliation: Department of Clinical and Community Sciences, University of Milan, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Barbieri
authors.affiliation: Endocrine and Diabetology Unit, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy ; Department of Clinical and Community Sciences, University of Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Spada
keywords: CASR; calcium metabolism; calcium sensing receptor; cinacalcet; ronacaleret