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Published byRosaline Simpson Modified over 9 years ago
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By Prof. Omnia Nayel Assoc. Prof. Osama Yousif
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By the end of this lecture you will be able to : Classify receptors into their main superfamilies Identify the nature & time frame of their response Recognize their different transduction mechanism ilo s
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1. Recognition 2. Reception 3. Transduction 4. Response A RECEPTOR Coupler Transduction Direct Its Structure: 1 2 3 4
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Location Structure Transduction Mechanism Classified according to their Time scale of Response 4 Main SUPERFAMILIES Channel-Linked Receptor G-Protein Coupled Receptors Nuclear Receptors Enzyme-Linked Receptors Nature of Response
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ConductanceCell Signal Transcription & Translation Cell Signal Hours / Days Minutes / Hours 1234
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Channel-Linked Receptor 1 Ionotropic Receptor Ligand-Gated-Ion Channel Different from [Voltage-Gated ]Ion Channel That is activated by a change in action potential Not by occupancy of a ligand Involved in fast synaptic neurotransmittion occurring over milliseconds It is activated directly when a ligand comes to bind to receptors that are incorporated as part of its structure Examples; Nicotinic Ach receptor activated by Ach
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G- Protein G-Protein-Coupled Receptor Metabotropic Receptor Involved in less rapid transmission of Transmitters: Adrenaline at Adr R, Ach at mAch R …etc. Hormones; Glucagon Others; Peptides, Purines, …etc Go-between proteins Coupler Agonist 2 1. Agonist occupancy dissociates [ ] subunit, so GTP replaces GDP & go to activate effector 2. Agonist loss cleaves GTP by GTPase with return of GDP so [ ] bind again Is Composed of 3 subunits [ ] & Guanyle Di- Phosphate [GDP] a G-Protein
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G- Protein G-Protein-Coupled Receptor Metabotropic Receptor Go-between proteins Coupler Agonist 2 a G-Protein An enzyme 2nd messenger An enzyme coupled to 2nd messenger Activates a Kinase 1. Adenyl cyclase 1. Adenyl cyclase cyclic Adenosine Mono- Protein Kinase A [AC] [cAMP] [AC] Phosph [cAMP] [PKA] 2. Phospholipase C (PLC) [IP3] 2. Phospholipase C (PLC) Inositol triphsph. [IP3] Ca ++ intracellular CaM dependent PK [CAMPK] [DAG ] Diacyl Glycerol [DAG ] Protein Kinase [PKC] PHOSPHORYLATION OF TARGET PROTEINS RESPONSE acts on Phosph Inositol di-Phosph [PIP 2 ]
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ATP G-Protein 3 subunits [ ] + GDP R E G-Protein-Coupled Receptor Adenyle cyclase PKA
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ATP R E cAMP PKA P P P Channels Enzymes Cytoskeletal Proteins
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G- Protein G-Protein-Coupled Receptor Metabotropic Receptor Go-between proteins Coupler Agonist 2 a G-Protein An enzyme 2nd messenger An enzyme coupled to 2nd messenger Activates a Kinase 1. Adenyl cyclase 1. Adenyl cyclase c yclic Adnosine Mono- Protein Kinase A [AC] [cAMP] [AC] Phosph [cAMP] [PKA] 2. Phospholipase C (PLC) [IP3] 2. Phospholipase C (PLC) Inositol triphsph. [IP3] Ca ++ intracellular CaM dependent PK [CAMPK] [DAG ] Diacyl Glycerol [DAG ] Protein Kinase [PKC] PHOSPHORYLATION OF TARGET PROTEINS RESPONSE acts on Phosph Inositol di-Phosph [PIP 2 ]
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E Phospholipase C PIP 2 DAG Phosphatidic a Inositol ↑ G-Protein-Coupled Receptor IP 3 Ca ++ PKC +CaM Cytoskeletal Proteins Channels P P CAMPK P P Enzymes P
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m Ach; m 1, m 2, m 3, m 4 Adrenergic receptors; G-Protein-Coupled Receptor Different Classes of Receptors Different Receptors Subtypes Ach R n, m Adrenergic R & Difference in their related G-Protein Classes Are the Most Abundant Type Divided according to their α-subunits into G s, G i and G q G s and G i produce, respective, stimulation and inhibition of AC G q is linked to activation of PLC-IP 3 -Ca ++ CaM & PKC
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a 1 Adrenoceptors couple to G q to stimulate PLC. 2 Adrenoceptors couple to G i to inhibit AC. 1&2 Adrenoceptors couple to G s to stimulate AC ADRENOCEPTORS + + AC Adrenoceptor 2 Adrenoceptor Inhibitory ReceptorStimulatory Receptor Adr GsGs GiGi ↑ cAMP cAMP Adr
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M 1 & M 3 Ach receptors couple to G q to stimulate PLC M 2 & M 4 Ach receptors couple to G i to inhibit AC CHOLINERGIC RECEPTORS + + + + PLC GqGq GqGq BronchiBlood Vessel PLC Adrenoceptor M 3 Ach receptor Stimulatory Receptor ↑ Ca ++ Adr Ach ↑ Ca ++
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Complexity of a response is governed by many ligands, receptors & effectors
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Enzyme-Linked Receptors 3 Involved in slow action of; hormones (insulin), growth factors, cytokines, ….. Their cytosolic domain either: 1. Associate directly with an enzyme like guanyl cyclase [GC] as in atrial natriuretic peptide [ANP] receptor. 2. Possess intrisic kinase activity (as tyrosine or serine/threonine kinase) that can phosphorylate itself (autophosphorylation) & / or other proteins that dock or bind to it. Example; insulin receptor They control many cellular functions as motility, growth, different- iation, division & morphogenesis. This usually require many intracellular signaling steps that take time [min. to hrs.] to process.
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Enzyme-Linked Receptors 3 1.Guanyle cyclase-Linked Receptors They have a single transmembrane spanning element. These have integral intrinic guanylate cyclase activity. Their 2 nd messenger is cyclic guanyl mono-phosph. [cGMP] → activates PKG → to phosphorylate other down stream protein signaling molecules. ↑ cGMP Example [ANP] Receptor
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Phosphorylate other proteins that it docks Activated Receptor autophosphorylates Ligands dimerize receptors Tyrosine Kinase-Linked Receptors Enzyme-Linked Receptors 3 Phosphorylated docked proteins RESPONSE Example Insulin Receptor
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Non activated Insulin Receptor Activated Insulin Receptor Insulin INSULIN RECEPTOR Tyrosine Kinase-Linked Receptors Enzyme-Linked Receptors 3
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Nuclear Receptors 4 Are intra-cellularly located whether in cytosol or the nucleus. Their natural ligands are usually : Extracellular lipophylic hormones; steroids, thyroids, …etc Extracellular lipids; linolinic a., retinoic a. Phosphorylated protein end product of 2 nd messenger signaling Protein Transcription Translation Involved in regulation of PROTEIN SYNTHESIS → most slowest in action. They possess an area that recognizes specific DNA sequence in the nucleus which can bind it. This sequence is called a Responsive Element [RE] This means that the activated receptors are acting as TRANSCRIPTION FACTORS [TF] → expressing or repressing target genes.
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Nuclear Receptors 4 The activated GC R complex Up-regulates expression of anti- inflammatory proteins Represses expression of pro-inflammatory proteins by preventing the translocation of their transcription factors from the cytosol into the nucleus). GLUCOCORTICOID [GC] RECEPTOR proteins
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THYROID HORMONE RECEPTOR THYROID HORMONE RECEPTOR Nuclear Receptors 4
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