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Submitted on March 11, 2002
Accepted on September 5, 2002
1 Department of Endocrinology, Barts & the London, Queen Mary School of Medicine, London, UK; Department of Medicine, University of Conneticut Health Center, Farmington, CT; Department of Internal Medicine, University of Virginia Medical Center, Charlottesville, VA; Department of Physiology, Semmelweis University Faculty of Medicine, Budapest, Hungary.
* To whom correspondence should be addressed. E-mail: a.j.clark{at}mds.qmw.ac.uk.
A naturally occurring Adrenocorticotropin (ACTH) receptor (MC2R) mutation (F278C) has been identified in a subject with ACTH independent Cushing's syndrome. Functional characterization of this mutant receptor reveals that it is associated with elevated basal cAMP accumulation when compared with wild type receptor-expressing cell lines. Dose responsiveness is similar between wild type and mutant receptors in cell lines expressing similar numbers of binding sites. In view of the location of this mutation in the C-terminal tail of the MC2R, desensitization and internalization were investigated and found to be impaired. Inhibition of protein kinase A by H89 blocks wild type MC2R desensitization and also results in increased basal activity, as does alanine substitution of Ser 280 in the C-terminal tail. Alanine substitution of Ser 208, the consensus protein kinase A phosphorylation target in the 3rd cytoplasmic loop also results in a reduction in desensitization without significant change in basal activity or internalization. These findings suggest a novel mechanism is involved in the apparently constitutive activation of the MC2R in which failure of desensitization appears to be associated with enhanced basal receptor activity.
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