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Mechanisms of Disease: the adrenocorticotropin receptor and disease

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 282–290 (2006)Cite this article

Abstract

The action of the peptide hormone adrenocorticotropin (ACTH) to stimulate glucocorticoid production by the adrenal gland is an essential physiologic process, yet is dependent on a single unique genetic component—the ACTH receptor or melanocortin 2 receptor. Genetic defects that cause abnormalities in this receptor or in a protein required for its expression at the cell surface result in a potentially fatal disease (familial glucocorticoid deficiency). Overexpression of this receptor or inability to desensitize it is found in adrenal adenomas or hyperplasia associated with glucocorticoid overproduction (Cushing syndrome). These disorders are uncommon, but there are considerable data to show that the hypothalamo–pituitary–adrenal axis is overactive, or in some circumstances underactive, in more common situations including depressive illness and septic shock. The origin of these latter disturbances is undoubtedly complex and multifactorial, but there is good evidence that a component of this phenomenon is an altered responsiveness of the ACTH receptor to ACTH. Understanding the basis of ACTH responsiveness might, therefore, contribute to the understanding of disorders such as these and perhaps enable the hypothalamo–pituitary–adrenal axis to be manipulated beneficially in these circumstances.

Key Points

  • Adrenocorticotropin (ACTH) has a key role in mediating the stress response by acting on a unique membrane receptor in the adrenal gland to stimulate glucocorticoid production

  • Inactivating mutations in the ACTH receptor, or in an accessory protein essential for its expression on the cell surface, cause an inherited syndrome of ACTH insensitivity—familial glucocorticoid deficiency

  • Disturbances of ACTH-receptor expression or function are often found in benign and malignant adrenal neoplasms

  • Altered responsiveness to ACTH is often present as a secondary phenomenon in several common disorders including depressive illness and septic shock

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Figure 1: Single-gene disorders of the hypothalamo–pituitary–adrenal axis
Figure 2: The effect of adrenocorticotropin resistance on extra-adrenal sites

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Acknowledgements

The Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC) fund research in our laboratory.

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Authors and Affiliations

  1. postdoctoral researcher, in the Centre for Endocrinology,

    Adrian JL Clark & Louise A Metherell

  2. William Harvey Research Institute at Barts and the London, UK

    Adrian JL Clark & Louise A Metherell

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  1. Adrian JL Clark
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Correspondence to Adrian JL Clark.

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Clark, A., Metherell, L. Mechanisms of Disease: the adrenocorticotropin receptor and disease. Nat Rev Endocrinol 2, 282–290 (2006). https://doi.org/10.1038/ncpendmet0165

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