chapter 16

• Cell signaling


  Cells need to sense and respond to their environment
• Signal transduction


  The process of converting one type of signal into another
• A target cell converts an extracellular signal into an intracellular signal

  
• Signals can act over long or short range
• Examples of extracellular molecules used as signals

  • Proteins
  • Peptides
  • Amino acids
  • Nucleotides
  • Steroids
  • Fatty acid derivatives
  • Gases
• Each cell responds to a limited set of signals
• Different types of cells respond to the same signal in different ways
• The signal molecules work in combinations to regulate the behavior of the cell

  
• Receptor


  • Signal's target is a receptor protein
  • Each receptor is signal specific
  • Receptor performs the primary transduction step which is receiving the signal and then generating a new intracellular signal

  
• Classes of extracellular signals

  • Those that bind to cell surface receptors and activate intracellular enzymes
  • Those that bind to intracellular receptors that regulate gene expression

  
• Some hormones cross the plasma membrane and bind to intracellular receptors
• Steroid receptors


  Dimers of zinc-finger proteins that reside within the nucleus, except for the glucocorticoid receptor which resides in the cytosol until it binds its ligand

  
• Hormone receptors are capable of regulating gene transcription

  
• Nitric oxide


  Crosses plasma membrane and activates intracellular enzyme directly
• Nitric oxide crosses plasma membrane

  Activates guanylyl cyclase, leading to formation of cyclic GMP
• Increase in cyclic GMP causes muscles to relax, allowing the vessel to dilate so that blood flow through it more freely
• Viagra enhances penile erection by blocking degradation of cyclic GMP, prolonging the NO signal
• Nitroglycerin will dilate veins more than arteries, decreasing cardiac preload and leading to therapeutic effects during episodes of angina pectoris
• General principles of cell signaling

  • Signals can act over a long or short range
  • Each cell responds to a limited set of signals
  • A cell's response to a signal can be fast or slow
  • Some hormones cross the plasma membrane and bind to intracellular receptors
  • Some dissolved gases cross the plasma membrane and activate intracellular enzymes directly

  
• Intracellular signaling molecules


  Small molecules - cyclic GMP, cyclic AMP, Ca2+, proteins

  
• Molecular switches


  Many intracellular signaling proteins act as molecular switches - receipt of a signal switches them from an inactive state to an active state

  
• Two main classes of molecular switches

  • GTP-binding proteins (trimeric and monomeric)
  • GAP - GTPase activating proteins
  • GEF - guanine nucleotide exchange factor
• GTP-binding proteins hydrolyze their bound GTP to GDP, using their own intrinsic GTPase activity
• General principles of cell signaling

  • Cell-surface receptors relay extracellular signals via intracellular signaling pathways
  • Some intracellular signaling proteins act as molecular switches
  • Phosphorylation and dephosphorylation
  • GTP-GDP exchange

  
• Cell-surface receptor classes


  • Ion-channel-coupled receptors
  • G-protein-coupled receptors
  • Enzyme-coupled receptors

  
• 1. protein-coupled receptors


  Mediate responses to diverse extracellular signals, single polypeptide, seven-pass transmembrane receptor protein

  
• Stimulation of GPCRs activates G-protein subunits


  1. Receptor activates G-protein

  2. G-protein α-subunit switches itself off by hydrolyzing its bound GTP

  
• Cholera toxin acts on the G-protein, keeping it always on, resulting in diarrhea and dehydration
• Some G proteins directly regulate ion channels, slowing heart beat
• How G proteins activate membrane-bound enzymes

  • Adenylyl cyclase
  • Phospholipase C

  
• Cyclic AMP signaling pathway

  • Adenylyl cyclase synthesizes cAMP, cAMP phosphodiesterase degrades cAMP
  • Protein kinase A gets activated by cyclic AMP
• A rise in intracellular cyclic AMP can activate gene transcription
• Second messengers


  Small molecules like cAMP, NO, IP3, DAG that transmit the original signal inside the cell

  
• The inositol phospholipid pathway triggers a rise in intracellular Ca2+


  1. Phospholipase C cleaves PIP2 to IP3 and DAG

  2. IP3 triggers release of Ca2+ from ER lumen
• Rise in intracellular Ca2+ triggers many biological processes, like the change in egg surface when a sperm enters
• Ca2+ signal


  Ca2+ binds to calmodulin, the Ca2+-calmodulin complex activates CaM-kinase
• Effects of Ca2+ are mediated through Ca2+ binding proteins like calmodulin, important in neuronal activity
• Protein kinases in signaling cascades

  • PKA - protein kinase A activated by cyclic AMP
  • PKC - protein kinase C activated by Ca2+
  • CaM K - kinase activated by Ca2+-calmodulin