Research ArticleGPCR SIGNALING

A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin–biased signaling

See allHide authors and affiliations

Science Signaling  20 Feb 2018:
Vol. 11, Issue 518, eaan3714
DOI: 10.1126/scisignal.aan3714

GPCR signaling biased by a salt bridge

The calcium-sensing receptor (CaSR) is a G protein–coupled receptor (GPCR) that plays an important role in extracellular calcium homeostasis by stimulating intracellular calcium signaling and mitogen-activated protein kinase (MAPK) pathways. Mutations in CASR that specifically affect either intracellular calcium or MAPK signaling have been associated with inherited forms of hypocalcemia. Gorvin et al. identified a CASR mutation that results in an Arg-to-Gly substitution at amino acid residue 680 (R680G) in CaSR in a family with hypocalcemia. Functional analysis of CaSRR680G in cultured cells revealed that this missense mutation did not affect intracellular calcium signaling but enhanced the ability of CaSR to stimulate MAPK signaling through a mechanism that depended on the scaffolding protein β-arrestin rather than on G proteins. Structural modeling and mutational analysis demonstrated that the substitution likely disrupted a salt bridge in CaSR. These findings identify a structural feature of CaSR that is important for controlling signaling bias.

View Full Text