Key Concepts of Section 15.5

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Key Concepts of Section 15.5

G Protein–Coupled Receptors That Activate or Inhibit Adenylyl Cyclase

  • Ligand binding by G protein–coupled receptors that activate Gαs 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 Gαi results in the inhibition of adenylyl cyclase and lower levels of cAMP (see Figure 15-25).

  • Gαs·GTP and Gαi·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 Gs-coupled receptors is down-regulated by multiple mechanisms: first, the intrinsic GTPase activity of Gαs that converts the bound GTP to GDP is enhanced when Gαs binds to adenylyl cyclase (this occurs when many Gα·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).