Essential Endocrinology and Diabetes. Richard I. G. Holt

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

      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

      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.