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

FEBS Letters

Spiegel, Allen M.¹  Zhao, Xin-mei¹  Hauache, Omar¹  Goldsmith, Paul K.¹  Collins, Regina¹ 

[1]Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9N-222, Bethesda, MD 20892, USA

关键词: G protein-coupled receptor;    Constitutive activation;    Calcium-sensing receptor;    CaR;    Ca2+ receptor;    hCaR;    human Ca2+ receptor;    DMEM;    Dulbecco's modified Eagle's medium;    FBS;    fetal bovine serum;    ADH;    autosomal dominant hypocalcemia;    PI;    phosphoinositide;    GPCR;    G protein-coupled receptor;    ECD;    extracellular domain;    PCR;    polymerase chain reaction;    TM;    transmembrane domain;    mGluR;    metabotropic glutamate receptor;   

DOI  :  10.1016/S0014-5793(99)00368-3

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown