A missense mutation in the seventh transmembrane domain constitutively activates the human Ca2+ receptor.
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.
Zhao
X M
XM
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Hauache
O
O
Goldsmith
P K
PK
Collins
R
R
Spiegel
A M
AM
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
D002135:Calcium-Binding Proteins; D010716:Phosphatidylinositols