A missense mutation in the seventh transmembrane domain constitutively activates the human Ca2+ receptor

• Published in: FEBS letters Vol. 448; no. 1; pp. 180 - 184
• Main Authors: Zhao, Xin-mei, Hauache, Omar, Goldsmith, Paul K., Collins, Regina, Spiegel, Allen M.
• Format: Journal Article
• Language: English
• Published: England 01.04.1999
• Subjects: ADH, autosomal dominant hypocalcemia; Binding Sites; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Calcium-sensing receptor; CaR, Ca2+ receptor; Cell Line, Transformed; Cell Membrane - metabolism; Constitutive activation; DMEM, Dulbecco's modified Eagle's medium; ECD, extracellular domain; Enzyme-Linked Immunosorbent Assay; FBS, fetal bovine serum; G protein-coupled receptor; GPCR, G protein-coupled receptor; hCaR, human Ca2+ receptor; Humans; Hydrolysis; mGluR, metabotropic glutamate receptor; Mutation, Missense; PCR, polymerase chain reaction; Phosphatidylinositols - metabolism; PI, phosphoinositide; Signal Transduction; TM, transmembrane domain
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(99)00368-3

A missense mutation, A843E, in the seventh transmembrane domain of the human Ca2+ receptor, identified in a subject with autosomal dominant hypocalcemia, was found to cause a constitutive activation while at the same time lowering the maximal response of the receptor to Ca2+. A truncated human Ca2+ receptor lacking the majority of the N‐terminal extracellular domain failed to respond to Ca2+ despite an excellent cell surface expression. The A843E mutant version of this truncated receptor showed constitutive activation. These results identify A843 as a critical residue for maintaining the inactive conformation of the human Ca2+ receptor. Substitution of glutamate, but not lysine or valine, for alanine 843 leads to activation of the human Ca2+ receptor in a manner that no longer depends upon Ca2+ binding to the extracellular domain.