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 essential roles in endocrinology. For instance, steroidogenic factor 1 (SF1, also called NR5A1) is a critical mediator of endocrine organ formation. Without it, the anterior pituitary gonadotrophs, adrenal gland and gonad fail to develop. It is also critical for the ongoing expression of many important genes within these cell types (e.g. the enzymes that orchestrate steroidogenesis; Figure 2.6). A variant receptor with a similar expression profile is DAX1 (also called NROB1), mutation of which causes X‐linked congenital adrenal hypoplasia (i.e. under‐development). Duplication of the region that includes the gene encoding DAX1 causes male‐to‐female sex reversal (Chapters 6 and 7). Increasingly, endogenous compounds are being identified that occupy the three‐dimensional structure created by the ligand‐binding domain. Whether these substances are the true hormone ligands remains debatable.
Figure 3.16 Hormonal stimulation of intracellular phospholipid turnover and calcium metabolism. Phosphatidylinositol (PI) metabolism includes the membrane intermediaries, PI monophosphate (PIP) and PI bisphosphate (PIP2). Hormone action stimulates phospholipase C, which hydrolyzes PIP2 to diacylglycerol (DAG) and inositol triphosphate (IP3). IP3 mobilizes calcium, particularly from the endoplasmic reticulum. DAG activates protein kinase C and increases its affinity for calcium ions, which further enhances activation. Collectively, these events stimulate phosphorylation cascades of proteins and enzymes that alter intracellular metabolism.
Figure 3.17 Eicosanoid signalling. Arachidonic acid, released by phospholipase A2, is the rate‐limiting precursor for generating eicosanoid signalling molecules by cyclo‐oxygenase (COX) and lipoxygenase pathways. This example produces prostaglandin E2 (PGE2), but there are at least 16 prostaglandins, all structurally related, 20‐carbon, fatty acid derivatives. They are released from many cell‐types and exert paracrine and autocrine actions (e.g. the inflammatory response and contraction of uterine smooth muscle). Their circulating half‐life is short (3–10 min). Aspirin inhibits prostaglandin production at sites of inflammation. There are different forms of COX; until withdrawn due to side‐effects, inhibitors of COX‐2 were used as anti‐inflammatory agents.
Figure 3.18 Simplified schematic of nuclear hormone action. (a) Free hormone (a steroid is shown), in equilibrium with protein‐bound hormone, diffuses across the target cell membrane. (b) Inside the cell, free hormone binds to its receptor
