Signal Transduction Lecture Notes PDF

SIGNAL TRANSDUCTION  signal transduction Extracellular signals are converted into intracellular signals: A signaling molecule (ligand) reaches its target cell and binds to a specific receptor.  signal transduction...

SIGNAL TRANSDUCTION  signal transduction Extracellular signals are converted into intracellular signals: A signaling molecule (ligand) reaches its target cell and binds to a specific receptor.  signal transduction > - This activates a signaling cascade involving intracellular enzymes and molecules (second messengers), which again leads to a specific reaction. ↑ Via signal amplification, the number of signaling molecules is increased at every step of the signal cascade. TRIGGERS A CHAIN REACTION INSIDE The Oc THIS ALUD second ENAMES AND Molecules INVOLVING Response Which cause A specific MESSANCERS  signal transduction Receptor: Proteins that receive signals from outside of the cell by binding specific ligands, thereby initiating an intracellular signaling cascade. ICHAIN REACTION Cell surface receptors (membrane receptors): located in the cell membrane Intracellular receptors: located inside the cell Nuclear receptors :intracellular receptors that act inside the nucleus  signal transduction Ligand (first messenger): A chemical messenger that binds specifically to one receptor Second messenger: small molecules (e.g. cGMP, IP3, Ca2+ ions) that mediate the intracellular response to an extracellular stimulus  signal transduction Signaling cascade: The interconnection of individual steps in a signaling pathway. Signal amplification: The increase in the number of signaling molecules at every step of the signal cascade  signal transduction Extracellular messengers have to bind to a receptor to exert their effect. Lipophilic messengers can pass through the cell membrane and bind to intracellular receptors, hydrophilic messengers cannot pass through due to the lipophilic properties of the cell membrane. act on membrane receptors, which translate the signal of the extracellular messenger into an intracellular signal.  signal transduction Intracellular receptors receptors that are located inside the cell A lipophilic hormone diffuses through the cell membrane. Hormones and receptor form a complex. Hormone-receptor complex binds to hormone-responsive elements  signal transduction Cell surface receptors Hydrophilic hormones transmit signals by binding to receptors present in the cell membrane (= cell surface receptors). There are three types of cell surface receptors: G protein-coupled receptors Enzyme-linked receptors Ligand-gated ion channels  signal transduction G protein-coupled receptors Receptor structure Receptor with seven transmembrane helices Binding sites for ligands are found in extracellular regions or between helices. Has an intracellular binding site for the G protein  signal transduction G protein composed of three subunits α subunit: Binds GDP in the inactive state and GTP in the active state β subunit: stable complex with the γ subunit γ subunit: complex with the β subunit with a lipid anchor in the cell membrane  signal transduction G protein-coupled receptors The binding of an extracellular ligand causes a conformational change in the receptor. The receptor binds intracellularly to G protein. Activated G protein binds GTP instead of GDP. Three subunits of the G protein dissociate in a complex composed of β and γ subunits and the α subunit. GTPase: a small G protein composed of only an α subunit that functions independently to hydrolyze GTP to GDP and phosphate  signal transduction G protein-coupled receptors Gs proteins: stimulate adenylyl cyclase Gi proteins: inhibit adenylyl cyclase Gq proteins: stimulate phospholipase c  signal transduction Receptor tyrosine kinases (RTKs) Receptor structure: Extracellular domain Single transmembrane domain Intracellular domain with tyrosine kinase activity  signal transduction Receptor tyrosine kinases (RTKs) Receptor tyrosine kinases are transmembrane receptors that are generally activated by ligand-induced dimerization and autophosphorylation of cytoplasmic tyrosine residues, which triggers activation of downstream signaling cascades. Examples of ligands: insulin, growth factors (e.g., EGF, IGF, FGF, TGF)  signal transduction Non-receptor tyrosine kinases Receptor structure Membrane receptor without tyrosine kinase activity  signal transduction Non-receptor tyrosine kinases Activation principle: Ligand binding leads to receptor dimerization. Two neighboring tyrosine kinase domains of JAK phosphorylate each other (autophosphorylation) → JAK activation Development of binding sites for SH2 domains of signal proteins (STAT proteins). STAT dimers exert their effect directly in the nucleus  signal transduction Ligand-gated ion channels Cell surface receptors that act as ion channels Ligand binding → conformational change Pore opening enables ion movement (Na+, K+ Ca2+, Cl-) across the cell membrane. Altered membrane potential → rapid signal response  signal transduction Second messengers small molecules that mediate the intracellular response to an extracellular stimulus.  signal transduction cAMP (cyclic adenosine monophosphate) A membrane-bound adenylyl cyclase synthesizes cAMP from ATP Gs proteins: activate adenylyl cyclase → ↑ cAMP Gi proteins: inhibit adenylyl cyclase → ↓ cAMP cAMP is degraded by phosphodiesterase to adenosine monophosphate (AMP).  signal transduction cGMP (cyclic guanosine monophosphate) Synthesis: cGMP is synthesized from GTP by the guanylate cyclase. Activates cGMP-dependent protein kinase G in smooth muscle cells → inhibits Ca2+ outflow from the sarcoplasmic reticulum → ↓ intracellular Ca2+ → relaxed smooth vascular muscles → vasodilation Degradation: by phosphodiesterase  signal transduction cGMP (cyclic guanosine monophosphate) Degradation: by phosphodiesterase (PDE) PDE inhibitors are used in the treatment of: pulmonary hypertension erectile dysfunction (PDE-5 inhibitor sildenafil)  signal transduction Nitric oxide (NO) Short half-life Can freely diffuse across cell membranes Synthesized in the endothelial cells of blood vessels Activates enzyme guanylate cyclase, which is present in the cytosol and converts GTP into cGMP causes smooth muscle relaxation and subsequent dilation of blood vessels  signal transduction Inositol trisphosphate (IP3) Synthesis Activation of a Gq protein-coupled receptor Activation of phospholipase C (an enzyme that cleaves phospholipids) Cleaving of the membrane-bound phospholipids PIP2 (phosphatidylinositol 4,5-bisphosphate) into the second messenger IP3 (inositol triphosphate) and DAG (diacylglycerol)  signal transduction Inositol trisphosphate (IP3) activation of IP3 receptors at the membrane of the endoplasmic reticulum (ER) → Ca2+ release from the ER via the IP3 receptor-coupled calcium channel → ↑ intracellular Ca2+ concentration → smooth muscle contraction  signal transduction Ca2+ as a second messenger Intracellular Ca2+ levels are usually very low. Second messengers (such as IP3) or depolarization by action potentials result in opening of the Ca2+ channels in the membrane of cells or ER → Ca2 Examples of Ca2+-mediated effects ↓ Glycogen synthesis ↓ Cholesterol synthesis