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Celluláris jelátviteli mechanizmusok A sejt-sejt kölcsönhatás Szignáltranszdukció ef hi von two # mayy tevolsig ,...

Celluláris jelátviteli mechanizmusok A sejt-sejt kölcsönhatás Szignáltranszdukció ef hi von two # mayy tevolsig , vinerramnd jutt el celsejthet Tobbregtech- e. net jemechonizmusse von Stihsigea mikodesende test Koording laschof Belo dudlat - Tobi minigyde hormondat boodtanch a vecc A szinptiles hopes.. towolre vold Wildebe seit-sejt kontent jelleg jett. a. Alldo sinpstie elotti idugsgt hotvettemil adjedt , manonned ejogodone i , a fogado , stimpris utchi , mon tovabbit a jekt a tavoli celporthot. El kotel helgezhedik it a colsthet egystent diffictional jut el , a clsejthez A hoteli sejtik egymosve vold latoso e jelot. At immun tomodosso volonslednt. volanz ranzekeint a Gebetvebseitet egg petogen ↳jetlinhemtemelachaa hoteli katas actiben duffundolhatnot messtise bouyet" a A molculdhat gyasan JelwestikMlienzeman a sete? magd elbontich seten a , immobiliziladiat extrocelluldis/ motivon. vogy Az ellenttes hatassal bino motelelik sinten gotoljde a tooli latest , hotzchopsolodna a jehmdekulhot vog receptordhot. 1) A medictat termel sejte celsajtwayenott. Ke pesele dyan jelezet libosatoni ameyene sajat magule, At stomsfed setelene imzabolyokes a valartouch let negativ. bitdiltjet a Wild sejt sajat receptoraive t , mmmee Mild mikodik sejtenzikeli , mint , egg wo megfeld stem jetmolchulit endogen alvastdolyotd molekule. to i  A sejt-sejt kommunikáció lépései 1. Szignálképzés 2. Szignálkibocsátás 3. Szignáltranszport 4. Receptormediált szignáldetekció 5. Celluláris válasz 6. A szignál megszűntetése Negatív visszacsatolás Pozitív visszacsatolás  Egyféle vagy többféle jel? Adott szignál más sejten másként hat A szignálmolekulák célpontjai Receptorok és a fiziológiai válasz Agonisták, antagonisták Szignál amplifikáció Szignáltranszdukció Proteinfunkció ki-be kapcsolása A receptor-tirozin kinázok ligand általi aktivációja  A szignáltranszdukciós fehérjék csoportosulása az aktivált receptor citoplazmatikus végén ADP H O protein (CH2)3 ribosylation C NH2 NH O + − N C NH2+ O P O CH2 O H H O − NH H H O P O CH2 O OH OH H H O NH2 H H N OH OH N O NH 2 N O P O CH2 N − N N O O H H − O P O CH2 N N H H O NAD+ OH OH H H O (nicotinamide H H protein OH OH adenine H O dinucleotide) (CH2)3 ADP-ribosylated C NH NH2 protein Arg + C NH2+ N residue nicotinamide H NH2  Cholera toxin catalyzes covalent modification of Gsa a. ADP-ribose is transferred from NAD+ to an arginine residue at the GTPase active site of Gsa a. ADP-ribosylation prevents GTP hydrolysis by Gsa. The stimulatory G-protein is permanently activated. Pertussis toxin (whooping cough disease) catalyzes ADP- ribosylation at a cysteine residue of the inhibitory Gia a, making it incapable of exchanging GDP for GTP. The inhibitory pathway is blocked. ADP-ribosylation is a general mechanism by which activity of many proteins is regulated, in eukaryotes (including mammals) as well as in prokaryotes. A membránreceptorok főbb típusai 4th edition of Lodish…4 major classes of cell surface receptors  Hormone Function of NO Intracellular signaling molecule – Regulates blood vessel dilation – Serves as second messenger – Serves as an neurotransmitter – Operates locally, quicly is converted into nitrates or nitrites – Half-life ~ 5 – 10 s – Synthesised from Arg by nitric oxide synthase  NO – receptor - soluble guanylyl cyclase Soluble guanylyl cyclase Binding NO to the heme cofactor in the NO N-terminal domain Dimerisation of the C-terminal domain Activation of C-terminal domain and catalyses of GTP to cGMP conversion GTP cGMP – second messenger in the cells causes smooth muscle relaxation cGMP +PPi Adenylate Cyclase (Adenylyl cAMP NH2 Cyclase) catalyzes: ATP à cAMP + PPi N N Binding of certain hormones (e.g., epinephrine) to the N N outer surface of a cell activates Adenylate Cyclase H2 O 5' C 4' to form cAMP within the cell. H H 1' O H 3' 2' H Cyclic AMP is thus P O OH considered to be a second O O- messenger. Phosphodiesterase enzymes NH2 cAMP catalyze: cAMP + H2O AMP N N The phosphodiesterase that N cleaves cAMP is activated by N phosphorylation catalyzed by H2 O Protein Kinase A. 5' C 4' H H 1' O Thus cAMP stimulates its H 3' 2' H own degradation, leading to P O OH O rapid turnoff of a cAMP signal. O- Sokféle receptor, néhány másodlagos messenger  Phospholipase C Phosphatidylinositol Signal Cascades O O H2C O C R2 R1 C O CH O H2C O P O O− H 1 6 OH OH H OH 2 H 5 OH phosphatidyl- H H 3 4 inositol H OH Some hormones activate a signal cascade based on the membrane lipid phosphatidylinositol.  O O H2C O C R2 R1 C O CH O H2C O P O O− H 1 6 OH OPO32− H OH 2 OH H 5 H H PIP2 3 4 phosphatidylinositol- H OPO32− 4,5-bisphosphate Kinases sequentially catalyze transfer of Pi from ATP to OH groups at positions 5 & 4 of the inositol ring, to yield phosphatidylinositol-4,5- bisphosphate (PIP2). PIP2 is cleaved by the enzyme Phospholipase C. O Different isoforms O H2C O C R2 of Phospholipase R1 C O CH O C have different H2C O P O regulatory cleavage by H domains, & thus O− 1 6 Phospholipase C OPO32− respond to different OH H OH 5 signals. 2 OH H H H A G-protein, Gq PIP2 3 4 phosphatidylinositol- H OPO32− activates one form 4,5-bisphosphate of Phospholipase C.  OPO32− H 1 6 OH OPO32− O H OH 2 OH H 5 O H2C O C R2 H H R1 C O CH 3 4 H OPO32− H2C OH IP3 inositol-1,4,5-trisphosphate diacylglycerol Cleavage of PIP2, catalyzed by Phospholipase C, yields 2 second messengers: inositol-1,4,5-trisphosphate (IP3) diacylglycerol (DG). Diacylglycerol, with Ca++, activates Protein Kinase C, which catalyzes phosphorylation of several cellular proteins, altering their activity. ++ Ca calmodulin ++ IP3 Ca -release channel ++ endoplasmic Ca reticulum ++ Ca -ATPase ATP ++ ADP + Pi Ca Kalcium mint másodlagos messenger A jel megszűntetése: Transzmitterlebontás  A jel megszűntetése: Transzmitterfelvétel A jel megszűntetése: A receptor és a ligand együttes felvétele  Válaszmoduláció: receptor felvétele és kihelyezése (up- és downreguláció) THE NERVOUS SYSTEM AN EXQUISITE AND COMPLEX INFORMATION PROCESSING SYSTEM INPUT ANALYSI OUTPUT S S S External PERCEPTION Voluntary (Sensory) S WAKE/SLEEP (Motor) ATTENTION LEARNING & Internal DRIVE MEMORY Involuntary (Hormonal) S (Motor, CONCEPTUALIZATIO Physiology) N MOTIVATION EMOTIONS  NEURON AXO D SZÓM 0.1 - N 1,000 E A mm N D R I V T Akciós E Idő potenciál K 1 - 100 m/sec Az akciós potenciál egyirányú impulzus, amely az axon eredésétől a végződése felé terjed. A neuronok képesek sorozatos akciós potenciálokat kibocsátani akár 200 impulzus/ másodperc sebességgel is. GENERATION OF ELECTRICAL CURRENTS AT SYNAPSES AND ALONG AXONS Neurons are BATTERIES that store energy in the form of ION GRADIENTS and ELECTRICAL POTENTIALS across cell surface membrane outsid [ Na+ ]o = 130 [ K+ ]i = 5 e mM mM AXON [ Na+ ]i = 5 [ K+ ]i = 130 mM mM ION PUMPS transport ions against their concentration gradients to create ION GRADIENTS batteries Pumps are driven by energy from ATP hydrolysis ELECTRICAL CURRENTS are generated by the opening of ION-SELECTIVE CHANNELS, allowing flow of current as ions down their concentration and electrical potential gradients ACh ACh  closed depolarisation inactivate ope d n Conformational changes in the voltage-dependent sodium channel.  MYELIN ON AXONS AN INSULATING SHEATH TO SPEED AND ENSURE LONG-DISTANCE ACTION POTENTIAL PROPOGATION  THE SYNAPSE CONTACT BETWEEN NEURONS THAT MEDIATES COMMUNICATION axo-dendritic synapse V time axo-somatic synapse axon collateral A neuron can receive synaptic inputs from many other neurons (pyramidal neuron in cerebral cortex can have 1,000 synaptic inputs) A neuron’s axon can have collateral branches which synapse on different neurons (the action potential will propagate down all branches)  THE ELECTRICAL SYNAPSE DIRECT ELECTRICAL TRANSMISSION THROUGH GAP JUNCTIONS DENDRITE AXON TERMINUS + - V V time time presynaptic action potential postsynaptic potential Gap junctions allow free diffusion of ions between cells Electrical current from action potential travels through synapse THE CHEMICAL SYNAPSE NEUROTRANSMITTER RELEASE FROM PRESYNAPTIC TERMINAL INTO SYNAPTIC CLEFT DENDRITE AXON TERMINUS NT vesicles NT receptors......... V V time time presynaptic action potential postsynaptic potential Action potential triggers vesicle exocytosis Neurotransmitter binding to post-synaptic receptors triggers post-synaptic electrical response  EXCITATORY VS. INHIBITORY CHEMICAL SYNPASES SYNAPSE TYPE SCHEMATIC RENDITIONS EXCITATOR Y INHIBITO RY Neurotransmitter release at excitatory synapse favors action potential generation in post-synaptic Neurotransmitter release at inhibitory synapse cell discourages action potential generation in post-synaptic cell A NEURON MAY RECEIVE BOTH EXCITATORY AND INHIBITORY INPUTS MULTIPLE SYNAPTIC INPUTS ARE INTEGRATED TO SET THE FREQUENCY OF ACTION POTENTIAL GENERATION INPUT S RESPON SE  THE NERVOUS SYSTEM IS HARD-WIRED WITH ADAPTABLE FUNCTION INDIVIDUAL “A” INDIVIDUAL “B” EACH PERSON HAS ALMOST THE SAME NEURAL WIRING EXPERIENCE EXPERIENCE CHANGES STRENGTH OF SYNAPTIC CONNECTIONS BASIS OF LEARNING AND MEMORY? MUSCLE FIBERS, LIKE NEURONS, ARE EXCITABLE MUSCLE ACTION POTENTIALS TRIGGER CONTRACTION Action potential traveling through muscle fiber induces elevation in cytosolic Ca+2 ion concentration Ca+2 and ATP drive the sliding of myosin filaments along actin filaments, thereby causing contraction  THE NEUROMUSCULAR JUNCTION EXCITATORY SYNAPSE BETWEEN MOTOR NEURON AXON AND MUSCLE FIBER