signal transduction (2)

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powerpoint presentation signal transduction (2) dr. fiona murray school of medical sciences fmurray@abdn.ac.uk * reading/resource rang, dale and ritter. rang and dale’s pharmacology 8th edition: ch3 * outline – lecture 4 overview of signal transduction types of receptors ligand-gated ion channels g protein–coupled receptor g proteins effectors of g proteins second messengers (camp, ip3, dag, rhoa) tyrosine kinase linked receptors nuclear/intracellular receptors general summary * marinissen et al., trends pharmacol sci. (2001); 22(7), 368 g protein-coupled receptor signaling * targets for g proteins adenylyl cyclase membrane bound enzyme (gαs, gαi) phospholipase c membrane bound enzyme (gαq) rhogef (gα12/13) ion channels (all) second messenger – cyclic 3’, 5’ adenosine monophosphate (camp) second messengers - inositol phosphate (ip3) and diacylglycerol (dag) ca2+, k+ channels second messenger - rhoa βγ – adenyly cyclase, ion channels, gpcr kinase, pi3kγ, plcβ α these direct effectors feed into many other pathways, such as the mitogen-activated protein …

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mp formation atp acs camp activators: forskolin, colforsin daropate hydrochloride (nkh447, japan) * phosphodiesterases (pdes)- camp degradation camp 5’amp pdes 11 pdes characterized pdes differ in: sequence substrate specificity (camp/cgmp) regulation tissue/cell distribution clinically used inhibitors –sildenafil (pde5, cgmp), roflumilast (pde4, camp), theophylline (non-selective, both) * camp pde ac ?? the camp pathway: formation vs. degradation camp pde ac ?? * downstream mediators of camp na+, k+ ca2+ * protein kinase a pka phosphorylates proteins and also regulating transcription (creb) many levels of –ve feedback (*) * * * * gαs-coupled gpcr desensitization (β2-adrenoceptor) hypothetical time course of camp accumulation “resting” steady state camp levels in cell -agonist increases camp to a steady state (synthesis = degradation) camp time β2-ar desensitization 2 1 3 4 3. decreased -receptor-g protein interaction ( camp synthesis, -arrestin) 4. down-regulation of receptor number and increased pde activity (hydrolysis) * actions of increased camp increases …

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including cell growth and metabolism gpcr-gq-plc-ip3/dag * phospholipase c phosphatidyl inositol 4,5 bisphosphate (pip2) inositol 1,4,5 triphosphate (ip3) diacylglyercerol (dag) increases in intracellular ca2+ activation of protein kinase c phospholipase cβ (plc) phosphatidyl inositol cycle pip2:phosphatidylinositol biophosphate, ip3: inositol triphosphate, dag: diacylglycerol, pa: phosphatidic acid, ip: inositol 1-phosphate, plc: phospholipase c ip3 - releases intracellular ca++ dag - activates protein kinase c pip2 ip3* dag** ip pa plc phosphatases kinases * ip3 and ca2+ release gq plcβ dag ip3 ca2+ ca2+ cellular responses er ligand ip3r intracellular ligand gated ion channel on endoplasmic reticulum – mobilisation of ca2+ from intracellular stores ecf r ip3r ip4?? * actions of increased intracellular calcium muscle contraction (cardiac, skeletal and smooth muscle) (α1-adrenoceptors, muscarinic receptor, endothelin receptor) hormone release immune response – increases t cell proliferation release of neurotransmitters increased force of cardiac muscle contraction triggers migration of pkc to membrane * actions of …

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cilitates gdp-gtp exchange at rhoa: - activates rho-associated protein kinase (rock) * actions of increased rhogef activity contraction of smooth muscle proliferation of smooth muscle angiogenesis migration synaptic remodelling one gene…..one gpcr…..one g protein…..one response g protein-coupled receptor signaling 5-ht * second messengers and protein phosphorylation many receptor-effector interactions result in kinase activity kinase enzymes phosphorylate substrate examples: protein kinase a (pka) protein kinase c (pkc) cam kinase g protein-coupled receptor kinases (grk) tyrosine kinase kinases have different substrate specificities * phosphorylation/dephosphorylation protein protein -p atp adp adp atp kinase atp synthase / phosphatase * second messengers and protein phosphorylation * activation of adenylyl cyclase ceases. similar amplification probably occurs in signaling from receptors coupled to other g proteins and some other types of receptors whose activa- tion induces synthesis of second messengers. a second level of amplification is illustrated by the camp-mediated stimulation of glycogenolysis. as we just discussed, …

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inase, and glycogen phosphorylase—are in a 1:10:240 ratio, which dramatically illustrates the amplifica- tion of the effects of epinephrine and camp. although such a cascade may seem overcomplicated, it not only greatly amplifies an external signal but also allows an entire group of enzyme-catalyzed reactions to be coordi- nately regulated by a single type of signaling molecule. in ad- dition, the multiple steps between stimulus and final response offer possibilities for regulation by other signaling pathways, thereby fine-tuning the cellular response. we will encounter other examples of cascades in signaling pathways discussed in the next chapter. several mechanisms regulate signaling from g protein–coupled receptors several factors contribute to termination of the response to hormones recognized by "-adrenergic receptors and other re- ceptors coupled to gs. first, the affinity of the receptor for hormone decreases when the gdp bound to gs# is replaced with a gtp following hormone binding. this increase …

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powerpoint presentation signal transduction (2) dr. fiona murray school of medical sciences fmurray@abdn.ac.uk * reading/resource rang, dale and ritter. rang and dale’s pharmacology 8th edition: ch3 * outline – lecture 4 overview of signal transduction types of receptors ligand-gated ion channels g protein–coupled receptor g proteins effectors of g proteins second messengers (camp, ip3, dag, rhoa) tyrosine kinase linked receptors nuclear/intracellular receptors general summary * marinissen et al., trends pharmacol sci. (2001); 22(7), 368 g protein-coupled receptor signaling * targets for g proteins adenylyl cyclase membrane bound enzyme (gαs, gαi) phospholipase c membrane bound enzyme (gαq) rhogef (gα12/13) ion channels (all) second messenger – cyclic 3’, 5’ adenosine monophosphate (camp) ...

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