Another well-studied second messenger system involves hormonal stimulation of phosphoinositide hydrolysis (Figure 2–14). Some of the hormones, neurotransmitters, and growth factors that trigger this pathway bind to receptors linked to G proteins, whereas others bind to receptor tyrosine kinases. In all cases, the crucial step is stimulation of a membrane enzyme, phospholipase C (PLC), which splits a minor phospholipid component of the plasma membrane, phosphatidylinositol-4,5-bisphosphate (PIP2), into two second messengers, diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3 or InsP3). Diacylglycerol is confined to the membrane, where it activates a phospholipidand
FIGURE 2–12 Rapid desensitization, resensitization, and down-regulation of β adrenoceptors. A: Response to a β-adrenoceptor agonist (ordinate) versus time (abscissa). (Numbers refer to the phases of receptor function in B.) Exposure of cells to agonist (indicated by the light-colored bar) produces a cyclic AMP (cAMP) response. A reduced cAMP response is observed in the continued presence of agonist; this “desensitization” typically occurs within a few minutes. If agonist is removed after a short time (typically several to tens of minutes, indicated by broken line on abscissa), cells recover full responsiveness to a subsequent addition of agonist (second light-colored bar). This “resensitization” fails to occur, or occurs incompletely, if cells are exposed to agonist repeatedly or over a more prolonged time period. B: Agonist binding to receptors initiates signaling by promoting receptor interaction with G proteins (Gs) located in the cytoplasm (step 1 in the diagram). Agonist-activated receptors are phosphorylated by a G protein-coupled receptor kinase (GRK), preventing receptor interaction with Gs and promoting binding of a different protein, β-arrestin (β-Arr), to the receptor (step 2). The receptor-arrestin complex binds to coated pits, promoting receptor internalization (step 3). Dissociation of agonist from internalized receptors reduces β-Arr binding affinity, allowing dephosphorylation of receptors by a phosphatase (P’ase, step 4) and return of receptors to the plasma membrane (step 5); together, these events result in the efficient resensitization of cellular responsiveness. Repeated or prolonged exposure of cells to agonist favors the delivery of internalized receptors to lysosomes (step 6), promoting receptor down-regulation rather than resensitization.
calcium-sensitive protein kinase called protein kinase C. IP3 is water-soluble and diffuses through the cytoplasm to trigger release of Ca2+ by binding to ligand-gated calcium channels in the limiting membranes of internal storage vesicles. Elevated cytoplasmic Ca2+ concentration resulting from IP3-promoted opening of these channels promotes the binding of Ca2+ to the calcium-binding protein calmodulin, which regulates activities of other enzymes, including calcium-dependent protein kinases.
With its multiple second messengers and protein kinases, the phosphoinositide signaling pathway is much more complex than
FIGURE 2–13 The cAMP second messenger pathway. Key proteins include hormone receptors (Rec), a stimulatory G protein (Gs), catalytic adenylyl cyclase (AC), phosphodiesterases (PDE) that hydrolyze cAMP, cAMP-dependent kinases, with regulatory (R) and catalytic (C) subunits, protein substrates (S) of the kinases, and phosphatases (P’ase), which remove phosphates from substrate proteins. Open arrows denote regulatory effects.