peptide (PTHrP)
For signalling by SS, vasopressin, AII, calcitonin and PTH/PTHrP, different receptor subtypes, potentially in different tissues, determine α‐subunit specificity. This provides opportunities for selective antagonist therapies.
Diacylglycerol and Ca 2+
Signalling from hormones, such as TRH, GnRH and oxytocin, recruits G‐protein complexes containing the Gqα subunit. This activates membrane‐associated phospholipase C, which catalyses the conversion of PI 4,5‐bisphosphate (PIP2) to DAG and IP3 (Figures 3.11 and 3.16). IP3 stimulates the transient release of calcium from the endoplasmic reticulum to activate several calcium‐sensitive enzymes, including isoforms of protein kinase C (PKC), and proteins like calmodulin (Figure 3.16). Calcium ions also activate cytosolic guanylate cyclase, an enzyme that catalyzes the formation of cyclic guanosine monophosphate (cGMP). The effects of atrial natriuretic peptide (ANP) are mediated by receptors linked to guanylate cyclase.
The major target of DAG signalling is PKC, which activates phospholipase A2 to liberate arachidonic acid from phospholipids and generate potent eicosanoids, including thromboxanes, leukotrienes, lipoxins and prostaglandins (Figure 3.17). The latter are well‐recognized paracrine and autocrine mediators capable of amplifying or prolonging a response to a hormonal stimulus.
Figure 3.12 Hormonal activation of G‐protein–coupled receptors can link to different second messenger pathways. The two alternative pathways are not mutually exclusive and may, in fact, interact.
Box 3.8 Defects in the G‐protein–coupled receptor/G‐protein signalling pathways
Several endocrinopathies occur because of activating or inactivating mutations in genes encoding GPCRs or G‐proteins coupled to them. Activating mutations cause constitutive overactivity; inactivating mutations cause hormone resistance syndromes characterized by high circulating hormone levels but diminished hormone action.
Gain of function
LH receptor: male precocious puberty (Figure 3.13)
TSH receptor: ‘toxic’ thyroid adenomas
Gsα: McCune–Albright syndrome (Figure 3.14), some cases of 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.
