Impaired desensitization of a mutant adrenocorticotropin receptor associated with apparent constitutive activity.

Abstract

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.

• Authors: Francesca M Swords, Asma Baig, Diana M Malchoff, Carl D Malchoff, Michael O Thorner, Peter J King, László Hunyady, Adrian J L Clark
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 16 Issue 12 Pg. 2746-53 (Dec 2002) ISSN: 0888-8809 [Print] United States
• PMID: 12456795 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Iodine Radioisotopes
• Receptor, Melanocortin, Type 2
• Receptors, Corticotropin
• Serine
• Adrenocorticotropic Hormone
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• Alanine

Topics

• Adrenal Cortex
• Adrenocorticotropic Hormone (metabolism, pharmacology)
• Alanine
• Animals
• Cell Line
• Cushing Syndrome (genetics)
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Enzyme Inhibitors (pharmacology)
• Gene Expression
• Humans
• Iodine Radioisotopes
• Kinetics
• Mice
• Mutation
• Phosphorylation
• Receptor, Melanocortin, Type 2
• Receptors, Corticotropin (drug effects, genetics, metabolism)
• Serine
• Signal Transduction
• Structure-Activity Relationship
• Transfection