A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate {beta}-arrestin-biased signaling

The calcium-sensing receptor (CaSR) is a G protein–coupled receptor (GPCR) that signals through Gq/11 and Gi/o to stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-function CASR mutations, which cause familial hypocalciuric hypercalcemia type 1 (FHH1) and autosomal dominant hypocalcemia type 1 (ADH1), respectively, have revealed that the CaSR signals in a biased manner. Thus,