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Signal transmission and signal transduction XIA Qiang, MD & PhD Department of Physiology Room 518, Block C, Research Building School of Medicine, Zijingang Campus Email: [email protected] Tel: 88206417 (Undergraduate school), 88208252 (Medical school) OUTLINE Intercellular signal transmission Chemical transmission Electrical transmission Signal transduction pathway Pathways initiated by intracellular receptors Pathways initiated by plasma membrane receptors Intercellular signal transmission Chemical transmission Chemical signals Neurotransmitters: Intercellular signal transmission Chemical transmission Chemical signals Neurotransmitters: Humoral factors: Hormones Cytokines Bioactivators Intercellular signal transmission Chemical transmission Chemical signals Neurotransmitters: Humoral factors: Gas: NO, CO, etc. Intercellular signal transmission Chemical transmission Chemical signals Receptors Membrane receptors Intracellular receptors Receptors on the surface of a cell are typically proteins that span the membrane Only Cell A has the matching receptors for this chemical messenger, so it is the only one that responds Cells B & C lack the matching receptors Therefore are not directly affected by the signal Intercellular signal transmission Electrical transmission Gap junction Cardiac Muscle Low Magnification View The intercalated disk is made of several types of intercellular junctions. The gap junction provides a low resistance pathway for the action potential to spread from cell to cell Signal transduction pathway Pathways initiated by intracellular receptors Pathways initiated by plasma membrane receptors This hydrophobic signal requires a carrier protein while in the plasma … … but at the target cell the signal moves easily through the membrane and binds to its receptor Signal transduction pathway Pathways initiated by intracellular receptors Pathways initiated by plasma membrane receptors (transmembrane signal transduction) Transmembrane signal transduction Transmembrane signal transduction Mediated by G protein-linked receptor Mediated by enzyme-linked receptor Mediated by ion channel Binding of ligands to membrane-spanning receptors activates diverse response mechanisms Transmembrane signal transduction Mediated by G protein-linked receptor Mediated by enzyme-linked receptor Mediated by ion channel The Nobel Prize in Physiology or Medicine 1994 "G-proteins and the role of these proteins in signal transduction in cells" Alfred G. Gilman Martin Rodbell The Discovery of G Proteins Normal Lymphoma Cell Mutated Lymphoma Cell Activation and Inactivation of the G Protein 1. The G protein, composed of alpha-, betaand gamma-subunits, in its resting state with bound GDP. 3. ...with GTP and the G proteins is activated. The subunits separate. 2. The receptor with bound hormone activates the G protein and replaces GDP... 4. Some seconds later the GTP, bound to the alpha-subunit, is hydrolysed to GDP. The subunits recombine. G-protein-coupled Receptors Signaling molecules involved G protein effector Second messenger Protein kinase Main signaling pathways (1) cAMP-PKA pathway (2) IP3-Ca2+ pathway (3) DG-PKC pathway (4) G protein-ion channel pathway (1) cAMP-PKA pathway Gs, Gi The cyclic AMP second messenger system Adenylyl cyclase forms cAMP, a “second messenger” that activates enzymes used in cellular responses The phosphodiesterase enzymes “terminate” the second messenger cAMP The cAMP system rapidly amplifies the response capacity of cells: here, one “first messenger” led to the formation of one million product molecules Cells can respond via the cAMP pathways using a diversity of cAMP-dependent enzymes, channels, organelles, contractile filaments, ion pumps, and changes in gene expression (2) IP3-Ca2+ pathway: Gq (3) DG-PKC pathway: Gq DAG: diacylglycerol IP3: inositol 1,4,5-trisphosphate PIP2: phospholipid phosphatidylinositol 4,5-bisphosphate This receptor-G-protein complex is linked to and activates phospholipase C, leading to an increase in IP3 and DAG, which work together to activate enzymes and to increase intracellular calcium levels Click here to play the Membrane Bound Receptors, G Proteins, and Calcium Channels Flash Animation (4) G protein-ion channel pathway Binding of the ligand to the receptor alters the receptor’s shape, which activates an associated G-protein, which then activates effector proteins, i.e., enzyme functions or ion channels The calcium-calmodulin system is similar to some of the cAMP pathways, because it results in the activation of protein kinases that can phosphorylate key proteins required for cellular responses The “arachidonic acid cascade” is activated in inflammation responses; “cox inhibitors” block cyclooxygenase Not all responses to hydrophilic signals are immediate: Increases in gene expression can occur, and the resulting proteins can increase the target cells’ response Eicosanoid: A lipid mediator of inflammation derived from the 20-carbon atom arachidonic acid (20 in Greek is "eicosa") or a similar fatty acid. The eicosanoids include the prostaglandins, prostacyclin, thromboxane, and leukotrienes. Transmembrane signal transduction Mediated by G protein-linked receptor Mediated by enzyme-linked receptor Mediated by ion channel Binding of the ligand to the receptor alters the receptor’s shape, which activates its enzyme function, phosphorylating an intracellular protein (1) Tyrosine Kinase Receptor Insulin receptor Growth factor receptor Mitogen-activated protein kinase (MAPK) pathway •PTK: protein tyrosine kinase •Ras: G protein. It consists of an a subunit, b subunit, and g subunit •MAPKKK: MAPK kinase kinase •MAPKK: MAPK kinase •MKP: MAPK phosphatases •TF: tissue factor (2) Receptor-associated tyrosine kinase JAK stands for Janus kinase or Just Another Kinase JAK2=Tyrosine protein kinase 2 Binding of the ligand to the receptor alters the receptor’s shape, which activates an associated enzyme function, phosphorylating an intracellular protein (3) Receptor guanylyl cyclase Soluble GC Transmembrane signal transduction Mediated by G protein-linked receptor Mediated by enzyme-linked receptor Mediated by ion channel Binding of the ligand to the receptor alters the receptor’s shape, which then opens (or closes) an ion channel N2-ACh receptor channel Any other pathway else? ? ? Pheromone Pheromones are chemicals emitted by living organisms to send messages to individuals of the same species. The male silk moth bombyx mori (Fig. 1, left) can detect very low quantities of the sex pheromone bombykol emitted by the female, and at the same time distinguishes bombykol from many other, often similar, volatile compounds in the air. A first step of olfaction is the tranfer of bombykol to the pheromone receptor at the neuronal membrane via the pheromone-binding protein (BmorPBP). Highly efficient uptake and release kinetics of bombykol at the pheromone binding protein is essential for olfactory function. However, BmorPBP features a central hydrophobic binding cavity for bombykol, completely encapsulating the ligand (Fig. 1, right) and the exit/entrance gate for bombykol is not known. Yet, the ligand has to enter and exit the cavity fast and reversibly. THANK YOU FOR YOUR ATTENTION!