In the absence of a ligand, heterotrimeric G proteins are inactive because the α subunit binds to GDP. When a signal molecule binds to an inactive G protein-coupled receptor (GPCR), it causes a change in the G protein that promotes the release of GDP and the subsequent binding of GTP to the α subunit. This stimulates the dissociation of the α subunit from the heterotrimeric complex and the release of the α subunit from the βγ dimer. The α subunit and βγ dimer can then interact with and regulate downstream effectors. GPCR kinase/β-arrestin inactivation leads to the removal of GPCRs from the plasma membrane and is an important mechanism for downregulating a response during prolonged exposure to elevated hormone levels. β blockers, given for congestive heart failure, reverse chronic desensitization and the associated recovery of adrenergic responsiveness.

Activated G protein α subunits interact with various effector proteins, such as adenylyl cyclase, phosphodiesterases, and phospholipases (A2, C, and D). Adenylyl cyclase is a common downstream effector of heterotrimeric G proteins. When a signal molecule binds to a GPCR that interacts with an αs class G protein, adenylyl cyclase is activated, leading to an increase in cAMP levels and the activation of protein kinase A (PKA). PKA phosphorylates specific serine and threonine residues on downstream effector proteins to regulate their activity. On the other hand, when a ligand binds to a receptor that interacts with an αi class G protein, adenylyl cyclase is inhibited, resulting in reductions in cAMP levels and PKA activity.

Some effector proteins, like ion-gated channels, are directly regulated by cAMP. cAMP is degraded to AMP by cAMP phosphodiesterases, which are inhibited by caffeine and other methylxanthines. By interfering with CREB protein, caffeine can prolong a constitutive "off" signal and phosphorylate and activate the transcription factor, thus stimulating gene transcription.
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