Principles of cell signaling - UT Southwestern

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39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 612 FIGURE 14.18 Activated PI 3- kinase phosphorylates PIP 2 to produce PIP 3 . The PH domain-containing protein kinases PDK1 and Akt bind to PIP 3 at the plasma membrane. Their colocalization facilitates the phosphorylation of Akt by PDK1. A second phosphorylation within a hydrophobic motif results in Akt activation by one of several candidate protein kinases. The Akt-2 isoform is required to elicit hallmark actions of insulin. p85 p110 PI 3-kinase PIP 2 PIP 3 strate most relevant to signaling functions. The functions of the phosphatidic acid product, which is also formed by phosphorylation of DAG, remain poorly understood but appear to include a role in secretion and the fusion of intracellular membranes. 14.17 PI 3-kinase regulates both cell shape and the activation of essential growth and metabolic functions Key concepts • Phosphorylation of some lipid second messengers changes their activity. • PIP 3 is recognized by proteins with a pleckstrin homology domain. Lipid second messengers may also be modified by phosphorylation. PI 3-kinase phosphorylates PIP 2 on the 3-position of the inositol ring to form PI 3,4,5-P 3 , another lipid second messenger. The total activity of PI 3-kinase is too low to significantly deplete total PIP 2 , but formation of small amounts of PIP 3 in localized membrane domains is vital for altering cell shape and cellular motility. PIP 3 acts by recruiting proteins that contain PIP 3 binding domains, including pleckstrin homology (PH) and FYVE domains, to sites where they regulate cytoskeletal remodeling, contractile protein function, or other regulatory events. These proteins anchor and/or orient the structural or motor proteins involved in cellular movement and localize signaling proteins to sites of action at the membrane. PIP 3 PIP 3 binding brings Akt and PDK1 to the membrane PIP 2 phosphorylated Akt Akt and PDK1 bind PIP3 through PH domains Akt PH domains PDK1 PDK1 Akt is activated by phosphorylation Other kinase Glucose uptake Glycogen synthesis Antilipolysis Antiapoptosis signaling can be fast and dramatic; it largely accounts for directing the mobility of motile mammalian cells. Lipid mediators are essential in the insulin signaling pathway. The binding of insulin stimulates the Tyr autophosphorylation of its receptor and the activation of effectors through insulin receptor substrate (IRS) proteins (see 14.30 Diverse signaling mechanisms are regulated by protein tyrosine kinases). PI 3-kinase is activated when its p85 subunit binds to IRS1. The PIP 3 generated by PI3- kinase binds the protein kinases Akt and phosphoinositide-dependent kinase-1 (PDK-1) via their PH domains. This interaction results in the localization of Akt to the membrane where it is activated by PDK1, as illustrated in FIGURE 14.18. Akt phosphorylates downstream targets, including protein kinases, GAPs, and transcription factors. Activation of Akt, specifically Akt-2, is required for the hallmark actions of insulin including regulation of glucose transporter translocation, enhanced protein synthesis, and expression of gluconeogenic and lipogenic enzymes. 14.18 Signaling through ion channel receptors is very fast Key concepts • Ion channels allow the passage of ions through a pore, resulting in rapid (microsecond) changes in membrane potential. • Channels are selective for particular ions or for cations or anions. • Channels regulate intracellular concentrations of regulatory ions, such as Ca2+. Ligand-gated ion channels are multisubunit, membrane-spanning proteins that create and regulate a water-filled pore through the membrane, as illustrated in the X-ray crystal structure of the nicotinic acetylcholine receptor in FIGURE 14.19. When stimulated by extracellular agonists, the subunits rearrange their conformations and orientations to open the pore and, thus, connect the aqueous spaces on either side of the membrane. The pore has a diameter that allows ions to diffuse freely from one side of the membrane to the other, driven by the electrical and chemical gradients that have been established by ion pumps and transporters. (For more about channel, pump and transporter mechanics see 2 Transport of ions and small molecules across membranes.) Channels maintain selectivity among ions by regulating the pore diameter precisely 612 CHAPTER 14 Principles of cell signaling
39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 613 and by lining the walls of the pore with appropriate hydrophilic residues. Receptor ion channels can, thus, provide a diffusion path for only cations or anions, or select among different ions. Ligand-gated ion channels provide the fastest signal transduction mechanism found in biology. Upon binding an agonist ligand, channels open within microseconds. At synapses, where neurotransmitters need to diffuse less than 0.1 micron, a signal in the postsynaptic cell can be generated in 100 microseconds. In contrast, receptor-stimulated G proteins require about 100 milliseconds to exchange GDP for GTP, and the action of receptor protein kinases is even slower. Ligand-gated ion channels are important receptors in many cells in addition to neurons and muscle, and other ion channels play equally vital roles in signaling pathways triggered by other classes of ligands. Ion channel signaling differs from that of the other receptors mentioned in this chapter in that there is no immediate protein target nor, in most cases, is there a specific second messenger involved. In most cases, channel-mediated ion flow acts to increase or decrease the cell’s membrane potential and, thus, modulates all transport processes for metabolites or ions that are electrically driven. Animal cells maintain an inside-negative membrane potential by pumping out Na + ions and pumping in K + ions (for more on membrane potential see 2.4 Electrochemical gradients across the cell membrane generate the membrane potential). The opening of a channel selective for Na+ will thus depolarize cells, and the opening of a channel for K + will hyperpolarize cells. Similarly, because Cl - is primarily extracellular, opening Cl - channels will also cause hyperpolarization. These electrical effects convey information to effector proteins that are energetically coupled to the membrane potential, or to specific ion gradients, or that bind a specific ion (such as Ca2+) whose concentration changes upon channel opening. The nicotinic acetylcholine receptor is the prototypical receptor ion channel and was the first receptor that was shown to be a channel. It is a relatively unselective cation channel that causes depolarization of the target cell by allowing Na+ influx. It is best known as the excitatory receptor at the neuromuscular synapse, where it triggers contraction, but alternative isoforms are also active in neurons and many other cells. In muscles, nicotinic depolarization acts via a voltage-sensitive Ca2+ channel to allow Ca2+ release from the sarcoplasmic reticulum into the cytosol. Calcium acts Nicotinic acetylcholine receptor structure CLOSED CYTOSOL Pore OPEN Pore FIGURE 14.19 The nicotinic cholinergic receptor is a cation-selective channel that is composed of five homologous but usually nonidentical subunits that oligomerize to form a primarily -helical membrane-spanning core. The channel itself is created within this core, and its opening and closing are executed by cooperative changes in subunit arrangement. Structure generated from Protein Data Bank file 2BG9. as a second (or third) messenger to initiate contraction (see 2.13 Cardiac and skeletal muscles are activated by excitation-contraction coupling). Nicotinic receptors promote exocytosis in some secretory cells by a similar mechanism, where Ca2+ triggers the exocytic event. In neurons, where nicotinic stimulation causes an action potential (depolarization that is rapidly propagated along the neuron), the initial depolarization is sensed by voltage-sensitive Na+ channels. Their opening (along with the action of other channels) propagates the action potential along the neuron. The nervous system is rich in receptor cation channels that respond to other neurotransmitters, the most common of which is the amino acid glutamate (Glu). The three different families of glutamate receptors share the property of cation conductance, but each family has its own spectrum of drug responses. All operate as neuronal activators, with one interesting twist: The NMDA family of receptors, named for their response to a selective drug, is permeant to Ca2+ in addition to Na+. A significant component of its activity is to permit the inward flow of Ca2+, which acts as a second messenger on a wide variety of targets. Persistant stimulation of NMDA channels by glutamate released during injury, or by drugs, can cause toxic amounts of Ca2+ to enter, resulting in neuronal death. A second functional group of receptor channels is selective for anions and, by allowing inward flux of Cl - , hyperpolarizes the target cell. Anion-selective receptors include those for γ- aminobutyric acid (GABA) and glycine (Gly). In neurons, hyperpolarization can inhibit the initiation of an action potential and/or neurotransmitter release. 14.18 Signaling through ion channel receptors is very fast 613
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