of C to C*.
Figure 3.11 Second messengers that mediate G‐protein–coupled receptor signalling. The symbol P is the abbreviation for a phosphate group. Carbon atoms are numbered in their ring position. R1 and R2 represent fatty acid chains.
Box 3.7 Sub‐families of Gα protein subunits
Gsα: activates adenylate cyclase
Giα: inhibits adenylate cyclase
Gqα: activates PLC
Goα: activates ion channels
Second messenger pathways
Cyclic adenosine monophosphate
Activation of membrane‐bound adenylate cyclase catalyzes the conversion of ATP to the second messenger cAMP (Figure 3.11). cAMP interacts with protein kinase A (PKA), which unmasks its catalytic site to allow phosphorylation of serine and threonine residues on a transcription factor called cAMP response element‐binding protein (CREB) (Figure 3.15). CREB then translocates to the nucleus where it binds to a short palindromic sequence in the regulatory regions of cAMP‐regulated genes. This signalling pathway controls major metabolic pathways, including those for lipolysis, glycogenolysis and steroidogenesis.
The cAMP response is terminated by a large family of phosphodiesterases, which can be activated by a variety of systems, including phosphorylation by PKA, in effect providing a negative feedback loop. Phosphodiesterases rapidly hydrolyze cAMP to the inactive 5′‐AMP. In addition, activated PKA can phosphorylate serine and threonine residues of the GPCR to cause receptor desensitization.
Table 3.1 Use of different G‐protein α‐subunits by various hormone signalling pathways
| Hormone | Dominant G‐protein α‐subunit(s) |
|---|---|
| Thyrotrophin‐releasing hormone (TRH) | Gqα |
| Corticotrophin‐releasing hormone (CRH) | Gsα |
| Gonadotrophin‐releasing hormone (GnRH) | Gqα |
| Somatostatin (SS) | Giα/Gqα |
| Thyroid‐stimulating hormone (TSH) | Gsα/Gqα |
| Luteinizing hormone (LH)/human chorionic gonadotrophin (hCG) | Gsα/Gqα |
| Follicle‐stimulating hormone (FSH) | Gsα/Gqα |
| Adrenocorticotrophic hormone (ACTH) | Gsα |
| Oxytocin | Gqα |
| Vasopressin | Gsα/Gqα |
| Catecholamines (β‐adrenergic) | Gsα |
| Angiotensin II (AII) | Giα/Gqα |
| Glucagon | Gsα |
| Calcium | Gqα/Giα |
| Calcitonin | Gsα/Giα/Gqα |
| Parathyroid hormone (PTH)/PTH‐related peptide (PTHrP) | Gsα/Gqα |
| Prostaglandin E2 | Gsα |
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