FSU PCB 3134 - GPCR and short-term cellular response

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Exam 3 I GPCR and short term cellular response 1 Signal transduction mediated by cell surface receptors general principle Cell Surface Receptors Consists of 3 segments Extracellular segment membrane spanning segment and intracellular segment Signaling molecule Ligand binds to a specific part of the receptor on the extracellular or membrane segment Signal Transduction The overall process of converting extracellular signals into intracellular responses General steps 1 Ligand is synthesized by a signaling cell and packaged into a secretroy vesicle 2 Ligand is released into extracellular space by exocytosis and transported to the target cell Usually a rise in the local concentration of Ca2 stimulates the exocytosis of the ligand into the surrounding medium or blood Signaling molecules can act locally or at a distince 2 3 Ligand binds to a specific cell surface receptor protein activation of receptor Binding of a ligand causes a conformational change in the membrane bound receptor enabling it to interact with other proteins which thereby initiates a downstream signal transduction cascade 4 Activated receptor initiates one or more intracellular signal transduction pathways Leading to 5 Specific short term changes in cellular function metabolism or movement Change in the activity or function of specific enzymes or other proteins that pre exist in the cell Usually a response to environmental stimuli 6 Long term changes in gene expression Changes in the amounts of specific proteins produced by a cell Usually the result of changes in the transcription of genes 7 Feedback regulation usually involving deactivation of the receptor 8 Signal molecule is removed and cellular response is terminated 1 Endocrine paracrine and autocrine signaling Signaling by extracellular molecules can be classified into four types based on the distance over which the signal acts 1 Endocrine Signaling Signaling molecules act on target cells DISTANT from their site of synthesis The sigaling molecues hormones are synthesized and secreted by endocrine They are transported through the circulatory system cells 2 Paracrine Signaling Signaling molecules act on target cells in close proximity from site of synthesis Ex Conduction by a neurotransmitter of a signal from one nerve cell to another or from a nerve cell to a muscle cell occurs via paracrine signaling Growth factors regulate development act short range Many development signals diffuse away from the signaling cell forming a concentration gradient and inducing different cellular responses depending on distance from target cell 3 Autocrine Signaling Cells respond to substances that they released themselves Ex Some growth factors can stimulate there own growth and proliferation This signaling is characterisitic of tumor cells 4 Signaling by plasma membrane attached proteins Signaling molecules are intergral membrane proteins located on the cell surface The membrane bound signals on one cell binds receptors on the surface of an adjacent target cell which triggers its differentiation Some signaling molecules can act at both short and long ranges Epinephrine Paracrine and Endocrine signaling iClicker lamellipodia are located at a cells leading edge 1 GPCR mechanisms of activation and termination 1 Trimeric G protein on off switch 1 Second messengers cAMP IP3 DAG General elements of G protein Coupled Receptors G protein Coupled Receptors most numerous class of receptors G protein coupled receptors Usually induce short term changes in cell function by modifying existing proteins Basically Receptor activation occurs when the ligand binds and triggers the activation of the coupled trimeric G protein which interacts with downstream signal transduction pathways All GPCR pathways contain same elements 1 Receptor with seven transmembrane domains 2 Coupled trimeric G protein functins as switch active inactive 3 Membrane bound effector protein 4 Feedback regulation and desensitization of the signaling pathway 5 Most have second messengers a 7 transmembrane alpha helical regions b Many subfamilies c The exterior surface of all G protein receptors is mostly hydrophobic amino acids that allow the protein to be anchored in the plasma membrane d The interior of the receptors is diverse allowing the different receptors to bind to different small molecules Ex Epinephrine Epinephrine is a important that acts in mediating the bodys response to stress fear or heave exercise When tissues may have an increased need to catabolize glucose and fatty acids to produce ATP these can be supplied to the blood by the rapid break down of glycogen to glucose in the liver and of triacylglycerols to fatty acids in adipose cells GPCR Pathway Overview 1 Extracellular primary signal activates receptor 2 Active receptor activates G protein 3 Active G protein activates effector enzyme 4 Active effector enzyme produces intracellular second messenger 5 Intracellular second messengers regulate downstream cellular responses Second messengers Ligands first messengers leads to a short lived increase in the concentration of intramolecular signaling molecules Second messengers They diffuse through the cytosol much faster than do proteins They are employed in pathways where the downstream target is located in a intracellular organelle distant from the PM receptor They facilitate amplification of an extracellular signal Activation of a single cell surface receptor molecule can result in a increase to thousands of a second messenger then each of those can activate a target protein Trimeric G protein G protein activation a Trimeric G proteins have three sub units and and are usually bound together and make the G subunit In OFF state G has a bound GDP and is complexed with G GPCR 1 Epinephrine a normal hormonal ligand binds to a GPCR and causes a change in the conformation of the cytosol facing loops and enables the receptor to bind to the G subunit 2 The binding releases the bound GDP Thus the activated ligand bound receptors acts as a guanine nucleotide exchange factor GEF for the G sub unit 3 GTP quickly binds to the empty guanine nucleotide site in the G sub unit causing a change in the conformation of its switch segments 4 These changes weaken the binding of G with the receptor and with the G subunit 5 The G GTP complex interacts with and activated an associated effector protein 6 The bound GTP is hydrolyzed back to GDP quickly catalyzed by the intrinsic GTPase activity of the G subunit The conformation of the G


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