CHAPTER 3 Signal Transduction, Membrane Receptors, Second Messengers, and Regulation of Gene Expression 45 • Fig. 3.9 Activation of a G Protein–Coupled Receptor (GPCR) and Effector Activation. In the absence of ligand, heterotrimeric G proteins are in an inactive state because GDP binds to the α subunit. Binding of a signal molecule to an inactive G protein–coupled receptor (GPCR) induces a conformational change in the G protein that promotes the release of GDP and the subsequent binding of GTP to the α subunit. Binding of GTP to the α subunit stimulates dissociation of the α subunit from the heterotrimeric complex and results in release of the α subunit from the βγ dimer, each of which can interact with and regulate downstream effectors. (Redrawn from Alberts B, et al: Molecular Biology of the Cell. 6th ed. New York:
Garland Science; 2015.) removal of the GPCR from the plasma membrane. GPCR kinase/β-arrestin inactivation with endocytosis of GPCRs is an important mechanism whereby cells downregulate (desensitize) a response during prolonged exposure to elevated hormone levels. One of the major benefits of β blockers, given for congestive heart failure, is that they reverse chronic desensitization and the associated recovery of adrenergic responsiveness.
Activated G protein α subunits couple to a variety of effector proteins, including adenylyl cyclase, phosphodiesterases, and phospholipases (A2, C, and D). A very common downstream effector of heterotrimeric G proteins is adenylyl cyclase, which facilitates the conversion of ATP to cAMP (
Fig. 3.10 ). When a signal molecule binds to a GPCR that interacts with a G protein composed of an α subunit of the αs class, adenylyl cyclase is activated, which causes an increase in cAMP levels and, as a result, activation of protein kinase A (PKA). By phosphorylating specific serine and threonine residues on downstream effector proteins, PKA regulates effector protein activity. In contrast, when a ligand binds to a receptor that interacts with a G protein composed of a α subunit of the αi class, adenylyl cyclase is inhibited, which causes reductions in cAMP levels and, consequently, in PKA activity.
Some effector proteins, such as ion-gated channels, are also regulated directly by cAMP. cAMP is degraded to AMP activated, phosphorylated CREB •Fig. 3.10 GPCR Stimulation of Adenylyl Cyclase, cAMP, and Protein Kinase A.Binding of a signal molecule to a GPCR mediates Gs stimulation of adenylyl cyclase, which increases cytosolic cAMP, which in turn activates protein kinase A (PKA). Activated PKA phosphorylates a number of target proteins to elicit many effects. PKA also enters the nucleus where it phosphorylates CREB (cyclic adenosine mono-phosphate [cyclic AMP] response element–binding protein). Phosphorylated CREB recruits coactivator CBP, which stimulates gene transcription. (Redrawn from Alberts B, etal: Molecular Biology of the Cell. 6th ed. New York: Garland Science; 2015.) by cAMP phosphodiesterases, which are inhibited by caf-and phosphorylate and activate the transcription factor feine and other methylxanthines. Thus by interfering with cAMP response element–binding (CREB) protein (see a constitutive “off” signal, caffeine can prolong a cellular