Key Concepts of Section 15.5

• Ligand binding by G protein–coupled receptors that activate G_αs results in the activation of the membrane-bound enzyme adenylyl cyclase, which converts ATP to the second messenger cAMP (see Figure 15-23). Ligand binding of G protein–coupled receptors that activate G_αi results in the inhibition of adenylyl cyclase and lower levels of cAMP (see Figure 15-25).

• G_αs·GTP and G_αi·GTP bind to the catalytic domain in adenylyl cyclase to activate or inhibit the enzyme, respectively (see Figures 15-25 and 15-26).

• cAMP binds cooperatively to a regulatory subunit of PKA, releasing the active kinase catalytic subunit (see Figure 15-27).

• In liver and muscle cells, activation of PKA induced by epinephrine and other hormones exerts a dual effect, inhibiting glycogen synthesis and stimulating glycogen breakdown via a kinase cascade (see Figure 15-28), leading to an increase in glucose for production of ATP.

• PKA mediates the diverse effects of cAMP in most cells (see Table 15-3). The substrates for PKA, and thus the cellular responses to hormone-induced activation of PKA, vary among cell types.

• The signal that activates the GPCR/adenylyl cyclase/cAMP/PKA signaling pathway is amplified tremendously by second messengers and kinase cascades (see Figures 15-7 and 15-29).

• Activation of PKA often leads to phosphorylation of nuclear CREB protein, which, together with the CBP/P300 co-activator, stimulates transcription of genes, thus initiating a long-term change in the cell’s protein composition (see Figure 15-30).

• Localization of PKA to specific regions of the cell by anchoring proteins restricts the effects of cAMP to particular subcellular locations (see Figure 15-31).

• Signaling from G_s-coupled receptors is down-regulated by multiple mechanisms: first, the intrinsic GTPase activity of G_αs that converts the bound GTP to GDP is enhanced when G_αs binds to adenylyl cyclase (this occurs when many G_α·GTP complexes bind to their respective effector proteins); and second, PDE acts to hydrolyze cAMP to 5′-AMP, terminating the cellular response.

• Most GPCRs are also regulated by feedback repression, in which the end product of a pathway (e.g., PKA) blocks an early step in the pathway. As with rhodopsin, binding of β-arrestin to phosphorylated β-adrenergic receptors completely inhibits activation of coupled G proteins (see Figure 15-32).

• β-adrenergic receptors are deactivated by β-adrenergic kinase (BARK), which phosphorylates cytosolic residues of the receptor in its active conformation. BARK phosphorylation of ligand-bound β-adrenergic receptors also leads to the binding of β-arrestin and endocytosis of the receptors. The consequent reduction in the number of cell-surface receptors renders the cell less sensitive to additional hormone.

• The GPCR-arrestin complex functions as a scaffold that activates several cytosolic kinases, initiating cascades that lead to transcriptional activation of many genes controlling cell growth (see Figure 15-32).