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Impaired Desensitization of a Mutant Adrenocorticotropin Receptor Associated with Apparent Constitutive Activity

Department of Endocrinology (F.M.S., A.B., P.J.K., A.J.L.C.), Barts & the London, Queen Mary School of Medicine, London EC1A 7BE, United Kingdom; Department of Medicine (D.M.M., C.D.M.), University of Connecticut Health Center, Farmington, Connecticut 06030; Department of Internal Medicine (M.O.T.), University of Virginia Medical Center, Charlottesville, Virginia 22908; and Department of Physiology (L.H.), Semmelweis University Faculty of Medicine, Budapest H-1444, Hungary

Address all correspondence and requests for reprints to: A. J. L. Clark, Department of Endocrinology, Barts & the London, Queen Mary School of Medicine, West Smithfield, London EC1A 7BE, United Kingdom. E-mail: a.j.clark{at}mds.qmw.ac.uk.

A naturally occurring ACTH receptor [melanocortin 2 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 third 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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