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Lecture 5

Lecture 5.docx

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University of Toronto St. George
Chris Garside

Lecture 5  Signal Transduction Pathways o Convert the change in receptor shape to an intracellular response o 4 Components  Receiver  Ligand-binding region of receptor  Transducer  Conformation change of the receptor which activates  Amplifier  Signal transduction cascade  Increases number of molecules affected  Responder  Molecular functions that change in response to signal  Transduction Pathway o Ligand binds to receptor and continues to activate o Amplification of molecules  Types of Receptors o Intracellular  Hydrophobic ligand  Used to cross membrane  Most for genomic effects o Ligand-gated ion channels  Changes in membrane potential  Rapid response o Receptor enzymes  Changes in membrane potential  Rapid o G-Protein coupled  Activation of G bound proteins  Rapid changes  Intracellular Receptors o Regulate transcription in target cells o Hydrophobic ligands the cell membrane o Inside the cell the ligand binds to ligand binding domain of intracellular receptors o Ligand binding changes conformation o Receptor-ligand complex translocate to the nucleus o DNA binding domain binds to DNA o Together it helps regulate the transcription of mRNA  Ligand gated ion channels o Ligand binds to transmembrane receptors o Receptors open o Travels down the electrochemical gradient o Direct and rapid  Receptor enzymes o Ligand binds to transmembrane receptors o Receptors dimerize and autophosphorylate o Protein kinases signals to Ras protein o Ras switches between active and inactive forms  G-protein coupled receptors o Ligand-receptor interacts with intracellular G-protein o Bond guanine nucleotides o Heterotrimetric o Ligand binds to a G-protein coupled receptors o Causes alpha subunit to release GDP and bind GTP o Activated alpha or beta-gamma subunits more through membrane to amplify enzyme o Activated amplifier enzyme converts an inactive second messenger into its active form o Subunits of the G-Protein  Activate ion channels  Activates amplifier enzyme: 2 messengers  Second Mesengers o A short lived intracellular messenger that acts as an intermediate in signal transduction pathway o Ca2+, cGMP, cAMP and phosphatidyl inositol Second Messenger Synthesized by the Action Effects enzyme Ca2+ None Binds to calmoduli Alters enzymes activity cGMP Guanylate Cyclate Activates protein Phosphorylate kinases (usually proteins. Open and protein kinase G) closes ion channels cAMP Adenylate Cyclase Activates protein Phosphorlytes kinases (usually proteins. Open and protein kinase A) closes ion channels Phosphatidyl Phospholipase C Activates protein Allows enzyme inositol kinase C. activity. Stimulates Ca2+ Phosphorylate release from proteins. intracellular stores Lignad binds  Inositol-Phospholipid Signaling o Ligand binds to a G protein, causing a conformational change o Alpha subunit of G protein is released and binds GTP and moves through the membrane o Activated alpha subunit activates phospholipase C, which cleaves PIP2 into IP3 and DAG o DAG is cleaved and forms arachidonic acid, the substrate for synthesis of chemical messengers called eicosanoids o IP3 is released into the cytoplasm o IP3 can be phosphorylated into IP4 o IP3 binds to Ca2+ channels on the endoplasmic reticulum o Ca2+ binds to calmodulin causing diverse effects o Ca2+ stimulates protein kinase C (PKC) and it interacts with DAG o DAG activates the PKC , which phosphorylates protein  Cyclic-AMP Signaling o Ligand binds to G protein and conformational change o The alpha subunit releases GDP binds to GTP move through the membrane and activates acetylates cyclase o Activates adenylase catalyze convert ATP to cAMP o cAMP binds to protein kinase A (PKA) dissociates from catalytic subunit o Activated catalytic subunit phosphorylate are dephosphorylated by serine/threonine phosphates o Ligand binds to G protein receptor the alpha subunit inhibits signal transduction pathways  Interaction Among Transduction pathways o Cells have receptor for different ligands o Response of the cell depends on complex interactions o Ex. Ca2+-CaM interacts with adenylate cyclase and cAMP PDE o PKA can phosphorylate Ca2+-channels  Regulation of cell signaling o Cell signaling is important for regulation of physiological processes o Components of biological control systems o 1. Sensor  Detects the level of a regulated variable
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