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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.