Adrenal Disorders Figure 1: Mechanism of Glucocorticoid Action OH O HO O CBG HLE O CBG-R OH O HO O OH
Extracellular space
OH O HO O 11β-HSD2 OH O 11β-HSD1 OH O O H HH O OH O HO O GR GRE Transactivation O GR O
GR p65
Transrepression
Cortisol binding globulin (CBG) limits access of the steroid to intracellular glucocorticoid receptors (GR). Both human leukocyte elastase (HLE) and cortisol binding globulin receptors (CBG-R) can increase cortisol delivery into the cell. Intracellular concentrations of cortisol are further influenced by the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD), which can increase (type 1) or decrease (type 2) cortisol levels. Cortisol binds to GR causing dissociation from heat shock proteins (HSPs) and subsequent translocation to the nucleus. Cortisol bound GR influences gene transcritpion either via an interaction between GR homodimers and glucocorticoid response elements (GREs) within genes (transactivation) or via the binding of GR monomers to relevant transcription factors (transrepression).
OH HO Cortisone OH O OH HO OH O OH Nucleus Mechanism of Glucocorticoid Action
GCs act mainly via intracellular receptors, of which there are two main types: the mineralocorticoid receptor (MR) and the GC receptor (GR). These receptors mostly act as transcription factors, regulating the expression of specific target genes. The number of target genes is large – possibly as high as 1% of the genome. MR is a high-affinity receptor that cannot distinguish cortisol from the mineralocorticoid aldosterone. The MRs have a highly tissue-specific pattern of expression, and in tissues classically associated with aldosterone actions (e.g. kidney) are protected from cortisol by 11β−HSD2. By contrast, the GR is a low-affinity receptor with a high specificity for GCs. It is widely distributed in the body. In many tissues, particularly those associated with metabolism (e.g. liver), access of cortisol is facilitated by 11β-HSD1.
in man; variations in pulse amplitude over the 24-hour cycle underpin the circadian profile of maximal GC levels in the morning, prior to awakening (approximately 800nM), and low levels in the evening (approximately 200nM).4–6
Plasma cortisol levels
are further increased by stress and, depending on the nature and intensity of the stress, may rise as much as ten-fold above basal levels.1
GCs in the bloodstream are largely bound to plasma proteins (~90%), in particular cortisol-binding globulin (CBG).7
Only the free steroid can
cross cell membranes and gain access to the intracellular receptors that mediate the biological effects of the steroids. Therefore, binding
48
Secretion of GCs into the circulation occurs in a pulsatile and circadian fashion. Pulse frequency is approximately one to three pulses per hour3
induces a conformational change that promotes the dissociation of the heat shock proteins, exposure of the nuclear localisation signal and translocation of the ligand–receptor complex to the nucleus via an importin-mediated mechanism.15
Ligand-bound
GR uses two principal mechanisms to influence transcription of specific target genes: transactivation and transrepression. Transactivation requires homodimerisation of GR subunits and interaction of the GR DNA-binding domain with conserved GC response elements within the promoter region of responsive genes,16 a process facilitated by the recruitment of transcriptionally active proteins.14
Interestingly, it appears that small changes in the DNA EUROPEAN ENDOCRINOLOGY
GRs are cytoplasmic receptors that, in the absence of ligand, exist in a complex with accessory proteins, such as heat shock proteins, which act as chaperones to retain the GR within the cytoplasm.13 Binding of cortisol to the ligand-binding domain within the C-terminal of GR14
OH O GR HSP HO OH OH Cytoplasm
Two further mechanisms determine the bioavailability of free cortisol within the cell. The first, termed pre-receptor ligand metabolism, is mediated by two intracellular enzymes, 11β- hydroxysteroid dehydrogenase 1 and 2 (11β-HSD1 and 11β-HSD2), which regulate the interconversion of cortisol and its biologically inert metabolite, cortisone. 11β-HSD1 acts as a reductase and thus regenerates bioactive cortisol from inactive cortisone and increases the local cortisol concentration. Conversely, 11β-HSD2 catalyses the conversion of cortisol to cortisone and thus reduces the availability of cortisol within the cells. These two enzymes are expressed in a highly tissue-specific manner. 11β−HSD1 is particularly prevalent in GC-responsive metabolic tissues such as the liver and central nervous system,10,11
while 11β-HSD2 is predominantly located within the kidney and protects high-affinity mineralocorticoid receptors from cortisol.10,12
The second mechanism is the multidrug-resistant drug (mdr) transporter protein, P-glycoprotein, which is also expressed in a highly tissue-specific manner and exports cortisol from cells, thus reducing the intracellular concentration of the steroid. The tissue-specific patterns of expression of 11β-HSD1, 11β-HSD2 and P-glycoprotein thus provide effective mechanisms for local regulation of the access of GCs to their receptors.
OH O Cortisol HO OH O OH OH O HO OH Capillary
In addition, some tissues possess membrane-bound CBG receptors, which can internalise both the binding protein and the associated cortisol (see Figure 1).9
to plasma proteins limits the access of circulating GCs to their receptors by restricting entry to target tissues. However, in certain conditions (e.g. inflammation), cortisol may be released from CBG in the target tissues by the actions of human leukocyte elastase, which cleaves CBG.8
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