Essential Endocrinology and Diabetes. Richard I. G. Holt
acromegaly and some autonomous thyroid nodules
Loss of function
V2 receptor: nephrogenic diabetes insipidus (high vasopressin)
TSH receptor: resistance to TSH (high TSH)
Gsα: pseudohypoparathyroidism (Figure 9.7) and Albright hereditary osteodystrophy
Nuclear receptors
Nuclear receptors are the second superfamily of hormone receptor. They are classified by their ligands, small lipophilic molecules that diffuse across the plasma membrane of target cells. Once ligand‐bound, the receptors typically function as transcription factors bound to DNA to regulate gene expression (Figure 3.18). This need for transcription and translation to elicit an effect means that biological responses of nuclear receptors are relatively slow compared to cell‐surface receptor signalling.
Figure 3.13 Familial male precocious puberty (‘testotoxicosis’). This 2‐year‐old presented with signs of precocious puberty. Note the musculature, pubic hair and inappropriately large size of the testes and penis. He was the height of a 4‐year‐old. His overnight gonadotrophins [luteinizing hormone (LH) and follicle‐stimulating hormone] were undetectable as testosterone was arising autonomously from Leydig cells due to a gain‐of‐function mutation in the gene encoding the LH receptor (Box 3.8).
Distinct regions of nuclear receptors can be identified, for which evolutionary conservation can be as high as 90%, i.e. the receptors are structurally related (Figure 3.19). For one sub‐group of the superfamily, no clear‐cut endogenous ligands have been identified and they are termed ‘orphan’ nuclear receptors. In addition, some variant receptors have atypical DNA‐binding domains and potentially function via indirect interaction with the genome. All the different types of nuclear receptor are associated with endocrinopathies, usually due to loss of function.
The receptors predominantly function in the nucleus. Nuclear import and export is a common and important regulatory mechanism by controlling access to target DNA binding sites in promoters and enhancers (Chapter 2). This shuttling is exemplified well by the glucocorticoid receptor (Figure 3.18).
Target cell conversion of hormones destined for nuclear receptors
In many instances, the ligand for the nuclear receptor undergoes enzymatic modification within the target cell. This converts the circulating hormone into a more or less potent metabolite prior to receptor binding (Table 3.2). For instance, cortisol is metabolized to cortisone by type 2 11β‐hydroxysteroid dehydrogenase (HSD11B2). In kidney tubular cells, this inactivation preserves aldosterone action at the mineralocorticoid receptor (MR). Without this, cortisol, present in the circulation at much higher concentrations than aldosterone, might saturate the MR, causing inappropriate overactivity. Impaired function of HSD11B2 causes the syndrome of ‘apparent mineralocorticoid excess’ characterised by hypertension and hypokalaemia.
Figure 3.14 McCune–Albright syndrome. At 6 years of age, this girl presented with breast development and vaginal bleeding in the absence of gonadotrophins. An activating mutation in Gsα had created independence from melanocyte‐stimulating hormone (MSH) causing skin pigmentation (‘café‐au‐lait’ spots). The same mutation in the ovary had caused constitutive activation leading to premature breast development. In some cases, constitutive over‐activity can cause fibrosis dysplasia in the bones, cortisol excess in the adrenal cortex (Cushing syndrome) and thyrotoxicosis.
From Brook’s Clinical Pediatric Endocrinology, Sixth Edition, Charles G. D. Brook, Peter E. Clayton, Rosalind S. Brown, Eds. Blackwell Publishing Limited. 2009.
Figure 3.15 The activation of protein kinase A, a cAMP‐dependent protein kinase. The four‐subunit complex is inactive. When cAMP binds to the regulatory subunits (red), dissociation occurs so that the active kinase subunits (blue) are released to catalyze the phosphorylation of the cAMP response element‐binding protein (CREB). This activates CREB () so that it can bind to its DNA target, the cAMP response element (CRE), to switch on transcription of cAMP‐inducible genes. RNA POL, RNA polymerase.
Nuclear localization, DNA binding and transcriptional activation
In their resting state, unbound steroid hormone receptors associate with heat‐shock proteins, which obscure the DNA‐binding domain and prevent binding to target DNA sequences in the genome. Steroid binding causes conformational change, the dissociation of the heat‐shock proteins and reveals two polypeptide loops stabilized by zinc ions that are known as zinc fingers. Once two steroid receptors have dimerized, these zinc finger motifs bind to target DNA at the specific hormone response element (HRE) (Figure 3.20).
Prior to hormone binding, the thyroid hormone receptor (TR) is located in the nucleus and can bind to DNA at the thyroid hormone response element (TRE). In the absence of hormone, the TR dimerizes with the retinoid X receptor and tends to recruit nuclear proteins that inhibit transcription (co‐repressors). Binding of thyroid hormone causes dissociation of these factors in favour of association with transcriptional co‐activators, and a sequence of events that results in the recruitment of DNA‐dependent RNA polymerase and gene transcription (Figure 3.20 and Figure 2.2).
Resistance syndromes for nuclear hormone receptors are similar to those for cell‐surface receptors. Inactivating mutations reduce or abolish receptor function. This can occur by a range of mechanisms, such as reduced hormone binding, impaired receptor dimerization or decreased binding to the HRE. Ultimately, this tends to reduce negative feedback and raise circulating hormone levels. The latter are frequently a diagnostic pointer for hormone resistance syndromes (Table 3.3).
Orphan nuclear receptors and variant nuclear receptors
Some orphan and variant receptors play