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Signal Transduction Lecture 14
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Ligands & Receptors n Ligand l Neurotransmitters & drugs n Receptor proteins l ligand binds to multiple receptors n Binding site l specific point of ligand & receptor n Affinity l attraction l physical & electrical fit~
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Receptor Activation n Lock & Key Model n Structure-activity relationship l Physical & electrical fit l Affinity n Activation excitation or inhibition n Drugs l Change structure change affinity l Agonists activate l Antagonists no activation ~
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Chemical Signaling Mechanisms n Synaptic n Paracrine l Medium range intercellular signaling n Endocrine l Hormones via blood n Pheromones l Via air ~
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Signaling Pathways n Cell impermeant l Requires receptors in membranes n Cell permeant l Lipid soluble l Steroid hormones n Cell-associated signaling molecules l e.g., CAMs ~
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Receptor Types n Channel-linked receptors l Ionotropic n Enzyme-linked receptors l Protein kinases mostly l Neurotrophin-R n G-protein-coupled receptors l Metabotropic n Intracellular receptors l Activation by cell-permeant signals ~
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Metabotropic receptors n G protein-coupled receptors l requires GTP n Receptor indirectly controls channel l G protein-gated ion channels l 2d messenger systems n neuromodulation l slower action l changes in sensitivity of neuron ~
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G protein-gated Ion Channels n NT binds to receptor protein l activates G protein n G protein binds to channel l opens or closes l relatively fast u compared to 2d messenger systems ~
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G protein: direct control R G GDP
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G protein: direct control R G GTP GDP *
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G protein: direct control R G GTP Pore
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n NT = 1st messenger n Membrane-associated components l Receptor l Transducer l Primary effector n Intracellular l 2d messenger l Secondary effector ~ 2d Messenger Systems
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2d Messenger Targets n Enzymes l Modulate phosphorylation n Protein Kinases l activated by: Ca 2+, cAMP, DAG, etc. l Increase phosphorylation n Protein Phosphatases l Decrease phosphorylation l activated by Ca 2+ /calmodulin ~
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2d Messenger Targets: Nuclear Signaling n Modulates protein synthesis l Slow: 30-60 min n Transcriptional activator proteins l DNA RNA Proteins ~
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2d Messenger Systems n Slower & enduring changes l Multiple effectors n Signal amplification l 1 NE 1000s cAMP l 1000s cAMP 10,000s phosphates n Effects l Control channel l Alter properties of receptors l regulation of gene expression ~
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2d Messengers n Calcium (Ca 2+ ) l Target: calmodulin l Calmodulin protein kinases & phosphatases n Cyclic nucleotides l cAMP & cGMP l Target: protein kinases ~
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2d Messengers: Membrane Lipids n Precursor: PIP 2 u Phosphatidylinositol biphosphate l Cleaved by phospholipase C n Diacylglycerol l DAG Protein Kinase C (membrane) n Inositol triphosphate l IP 3 Ca 2+ (endoplasmic reticulum) ~
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adrenergic 2d Messenger System Receptor trans- ducer primary effector external signal: nt 2d messenger secondary effector Receptor trans- ducer primary effector external signal: nt 2d messenger secondary effector GSGS norepinephrine cAMP protein kinase adrenergic -R adenylyl cyclase
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adrenergic 2d Messenger System n NT: Norepinephrine n Membrane-associated components Receptor: adrenergic l Transducer: G s protein l Primary effector: Adenyly cyclase n Intracellular components l 2d messenger: cAMP l Secondary effector: Protein kinase ~
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G protein: Protein Phosphorylation R G GDP ACAC PK
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G protein: Protein Phosphorylation R ACAC PK G GTP ATP cAMP
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G protein: Protein Phosphorylation R ACAC PK G GTP ATP cAMP P
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G protein: Protein Phosphorylation R ACAC PK G GTP ATP cAMP P Pore
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