title: A missense mutation in the seventh transmembrane domain constitutively activates the human Ca2+ receptor.
abstract: 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.
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: X M
authors.initials: XM
authors.lastname: Zhao
authors.forename: O
authors.initials: O
authors.lastname: Hauache
authors.forename: P K
authors.initials: PK
authors.lastname: Goldsmith
authors.forename: R
authors.initials: R
authors.lastname: Collins
authors.forename: A M
authors.initials: AM
authors.lastname: Spiegel
mesh_terms: D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006868:Hydrolysis; D020125:Mutation, Missense; D010716:Phosphatidylinositols / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; D010716:Phosphatidylinositols