Signal Transduction 2024-2025 PDF

Block 1.2 lectures 2024-2025 signals transduction j Highlighter key Writer...

Block 1.2 lectures 2024-2025 signals transduction j Highlighter key Writer Reviewer Doctor explanation Abbreviation Key information Book >> >> Ahmed ALAhmed Student explaintion 221-222-223 notes References Deleted Mohammed ALibraheem Signal Transduction Dr.TarekBENAMEUR Department of Biomedical Sciences College of Medicine King Faisal University  Learning Objectives By the end of this lecture you are expected to know : General principles of cell signaling and Signal Transduction Types of intercellular signaling Chemical nature of some signal molecules Different responses of cells to the same signal molecule Molecular on/off switching in signal transduction Signal transduction through the various types of receptors  Lecture Outline Definitions General principles of cell signaling and Signal Transduction Types of intercellular signaling Chemical nature of some signal molecules Different responses of cells to the same signal molecule Molecular on/off switching in signal transduction Signal transduction through the various types of receptors  Definitions  Receptor protein: -proteinthat recognizes -binds a specific signal molecules -initiates a physiological response in the cell.  Extracellular(EC) signaling molecule: - Any molecule present outside the cell - elicits a response inside the cell when binds to a receptor protein  Intracellular(IC) signaling molecule: Molecule that is part of : the mechanism of transducing& transmittingsignal insidea cell  Lecture Outline Definitions General principles of cell signaling and Signal Transduction Types of intercellular signaling Chemical nature of some signal molecules Different responses of cells to the same signal molecule Molecular on/off switching in signal transduction Signal transduction through the various types of receptors  General Principles of Cell Signaling  Cell-cell communication: essential for unicellular & multicellular organisms to coordinate their behavior e.g. growth, development, differentiation, tissue & organ formation, maintenance, homeostasis & diseases processes. e.g. Fight-or-flight response is triggered by a signaling molecule (Epinephrine) This is just to give you an idea about cells communication, cells are communicating like human, but they have their own messages. And their messages should be exchanged in all directions as the arrows in the picture  Overview of Cell Signaling EXTRACELLULAR CYTOPLASM FLUID Plasma membrane 1 Reception Receptor Signaling molecule The signaling molecule (ligand) binds to the specific receptor protein (Reception)  Overview of Cell Signaling EXTRACELLULAR CYTOPLASM FLUID Plasma membrane 1 Reception 2 Transduction Receptor Relay molecules in a signal transduction pathw ay Once a cell receives a molecule, that molecule will go through three stages: Signaling 1- Reception molecule 2- transduction 3- response Reception sets off a relay team of communication proteinsin the cell  Overview of Cell Signaling EXTRACELLULAR CYTOPLASM FLUID Plasma membrane 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules in a signal transduction pathw ay Signaling molecule Response: activation of gene, triggering apoptosis, enter mitosis,….  Signal Transduction 2-Here we have a extracellular signal molecule the first step in the next slide 3-after binding and reception by the cell Signal transduction: it’s converted into another form -Conversion of information from one forminto another -Begins when target cell: -receives an incoming EC signal and -converts it into IC signals that alter cell behavior *IC: Intracellular ; *EC: Extracellular 1- This is just an example to understand the (signal transduction),, when you receive a call you hear a sound waves, but in the origin it’s not a sound waves it’s a radio signal. This radio signal after going inside the mobile phone it’s converted into a sound waves. So the process of conversion it’s like what happens inside the cell with signal transduction. So the signal transduction is Conversion of information from one form into another How Cells Communicate With Each Other In The Human Body ? As we use Arabic or English language to communicate, Cells use a signals to communicate to each other what are these signals we will discuss them in the next slide ?  Lecture Outline Definitions inter : between intra : inside General principles of cell signaling and Signal Transduction Intercellular signalling :does not means signals inside the cell Types of intercellular signaling It means signals between the cells Chemical nature of some signal molecules Different responses of cells to the same signal molecule Molecular on/off switching in signal transduction Signal transduction through the various types of receptors Types of Intercellular Signaling  Endocrine is the most common type. Paracrine: Involves signaling cell It works by endocrine cells which responsible for which’s the principle of local secreting hormones , hormones travels throw blood mediator and many of signal ( systemic circulation) to reach to the targeted cells. molecules that are important in These targeted cells have specific receptors to bind regulation of the inflammation specifically at the site of infection with these hormones to induce wanted things or and controlling the cell proliferation function. for process of wound healing. It could be also autocrine. Autocrine means the cell secretes mediators and these mediators will affect the same cell that secreted the mediators Contact-dependant means Neural : it is involved in neurons through contacting of two cells For example : Once spinal cord send signals to by the membrane bound signal the peripheral part, these signals will be traveled ‫كأنه استلام باليد‬ along the axon which may be measured 1.5m, ‫ بيدها‬signal ‫يعني كأن الخلية تسلم ال‬ and when these signals reach to terminal of the ✋ ‫الى يد الخلية الثانية‬ axon, there will be conversion of these signals, and they will be released to the synapse and will induce effect in the targeted cell. Without secreting any molecule  Lecture Outline Definitions General principles of cell signaling and Signal Transduction Types of intercellular signaling Chemical nature of some signal molecules Different responses of cells to the same signal molecule Molecular on/off switching in signal transduction Signal transduction through the various types of receptors ExaEmxpalmesp olfe Ssig onaf lS Migonle Nature 1/2 The doctor said: you can read the whole table in your home. He just focused on the 3 highlighted hormones ( Epinephrine- cortisol-insulin) ExaEmxpalmesp olfe Ssig onaf lS Migonle Nature 2/2  Lecture Outline Definitions General principles of cell signaling and Signal Transduction Types of intercellular signaling Chemical nature of some signal molecules Different responses of cells to the same signal molecule Molecular on/off switching in signal transduction Signal transduction through the various types of receptors  Signaling Molecules May Induce Different Responses In Different Cell Types 1/2 Acetylcholine Acetylcholine: when it binds to the heart pacemaker cell will decrease the rate of firing Also it will slow the heart rate by activating M2 acetylcholine receptor And the same molecule acetylcholine when it binds to skeletal muscle cell will induce the contraction And when acetylcholin binds to salivary gland cell will enhance the secretion of saliva The same signal molecule can cause different responses in different target cells, Why ? We will know the answer in the next slide Signaling Molecules May Induce Different Responses In Different Cell Types 2/2 Different responsesof cells to the samesignal molecule: Why ? The set of receptors the cell possesses for the signal The intracellular machinery : Integration & interpretation of signals  Two Classes of Signal Molecules  Hydrophilic or large: -Rely on Cell-surface receptors. not membrane- permeable e.g. growth factors Relay on central nerve receptors Hydrophobic or small: -Activate enzymes directly or bind to membrane-permeable Intracellular receptors. e.g. Steroid hormones Because they are membrane-permeable molecules ,they can directly activate downstream cascade or proteins or also enzymes. And bind to nuclear receptors ( intracellular receptors)  Example: Steroid Hormones Signal Through Intracellular Receptors Hydrophobic Cortisol cross the membrane, binds with nuclear receptor or cytosolic receptor it doesn’t matter is long is this receptor will move to the nucleus, after conformational changes (then it becomes activated) and it will move inside nucleus and will bind to specific region it’s called regular generation of the target cell and it will induce transcription  Nitric Oxide Crosses The Plasma Membrane & Activates Intracellular Enzymes Directly  NO: chemically unstable gas; Small, half-life (5-10 sec)  Nitroglycerine(converted to NO) treating angina  Acetylcholine activates NOS Angina : when there is not enough blood that reach cardiac muscle cells) and it will increase som abnormalities Acetylcholine: Nitric Oxide NO: permeable non-permeable (At the level of endothelial cell Acetylcholine bind to receptor it will induce The activation of this receptor > this will activate No synthesis “ it’s an enzyme responsible for production nitric oxide from arginine > endothelial cells produce NO from arginine ) > NO of rapid diffusion it will go and bound to guanylyl cyclase = convert GTP to cyclic GMP and NO it’s permeable here > GMP it will induce smooth small muscle relaxation Acetylcholine: Nitric Oxide NO: permeable non-permeable  Cell-surface receptors relay the signal through intracellular signaling molecules Simple intracellular signaling binds pathway activates Signal transduced through chain reaction of signal molecules leading to final response (proteins or small messengers) e.g: kinases & G proteins interact  Lecture Outline Definitions General principles of cell signaling and Signal Transduction Types of intercellular signaling Chemical nature of some signal molecules Different responses of cells to the same signal molecule Molecular on/off switching in signal transduction Signal transduction through the various types of receptors Common Intracellular Signaling Proteins act as Molecular “Switches” Kinases G proteins  RTK signaling & G-protein-mediated signaling: Signaling protein -Activatedby phosphorylation -Inactivated by dephosphorylation  Common Intracellular Signaling Proteins act as Molecular “Switches” Kinases G proteins Kinase = add phosphate and activate. Phosphatase = release phosphate group and deactivate When there is signal molecule> GDP will be out and GTP will binding and it will be activated > when it’s not needed phosphate group will be out and GTP will hydrolysis and it will go in inactive state RTKsignaling & G-protein-mediated signaling: Signaling protein -Activatedby phosphorylation  -Inactivatedby dephosphorylation Signal ln from outside or neighbouring cells the protein kinase will be activated > ATP will enter and will give us phosphate and it will bind with receptor and it will activate this kinase whenever the cell don’t need the activation it will release the phosphate group >kinase will be off  Why Molecular Switches Are Important In Disease ? Bacteria toxin targets G-protein: CFTR Cholera toxin: - Prevents Gsfrom hydrolyzing its bunit GTP-bound -Excessive Cl-& H2O outflow into the gut Catastrophic diarrhea, Dehydration CFTR : Cystic fibrosis transmembrane conductance regulator  Once cholera inter the body by drinking contaminated water, the bacteria will release toxin, will bind to the gangliosides receptors , and theses receptors transmit the signals inside downstream protein effector, then transduction of the signals will lead to excessive chloride outflow to the small intestine flowed be sodium and water. This cholera protein will prevent the G-protein specifically Gs form hydrolysis GTP bound , so it will kept active ( turned on ) Cholera toxin bind to Ganglioside receptor > signal transduction > signal reaches G protein > activate adenylyl cylase > ATP become cyclic AMP > activate protein kinase > Activate CFTR (cystic fibrosis transmembrane receptor) > outflow of electrolytes and water into lumin of small intestine old year but this from the book G proteins demonstrate a general principle of cell signaling mentioned earlier: the mechanisms that shut a signal off are as important as the mechanisms that turn it on. The shut-off mechanisms also offer as many opportunities for control—and as many dangers for mishap. Consider cholera, for example. The disease is caused by a bacte- rium that multiplies in the human intestine, where it produces a protein called cholera toxin. This protein enters the cells that line the intestine and modifies the α subunit of a G protein called Gs—so named because it stimulates the enzyme adenylyl cyclase, which we discuss shortly. The modification prevents Gs from hydrolyzing its bound GTP, thus lock- ing the G protein in the active state, in which it continuously stimulates adenylyl cyclase. In intestinal cells, this stimulation causes a prolonged and excessive outflow of Cl– and water into the gut, resulting in cata- strophic diarrhea and dehydration. The condition often leads to death unless urgent steps are taken to replace the lost water and ions. A similar situation occurs in whooping cough (pertussis), a common res- piratory infection against which infants are now routinely vaccinated. In this case, the disease-causing bacterium colonizes the lung, where it produces a protein called pertussis toxin. This protein alters the α subunit of a different type of G protein, called Gi, because it inhibits adenylyl cyclase. In this case, however, modification by the toxin disables the G protein by locking it into its inactive GDPbound state. Inhibiting Gi, like activat- ing Gs, results in the prolonged and inappropriate activation of adenylyl cyclase, which, in this case, stimulates coughing. Both the diarrhea- producing effects of cholera toxin and the cough-provoking effects of pertussis toxin help the Which of the following is most likely to  Lecture Outline Definitions General principles of cell signaling and Signal Transduction Types of intercellular signaling Chemical nature of some signal molecules Different responses of cells to the same signal molecule Molecular on/off switching in signal transduction Signal transduction through the various types of receptors Three Main Classes of Cell-Surface Receptors Ion-Channel-Coupled Receptors G-Protein-Coupled-Receptors (GPCRs) Enzyme-Coupled Receptors  Ion-Channel-Coupled Receptors Also known as : transmitter-gated ion channels When the signal molecules is bound to this specific receptor this will open the ion channels and the ions will pass through receptor however when the signal molecules is not bind to this receptor the gate will be close When there is movement of ions and the ions will be charged it could be positively charged or negatively charged this will affect the electrical signal between the outside side and inside of the cells Rapid synaptic signaling between electrically excitable cells Transduce chemical signals directly into electrical signals  G-Protein-Coupled Receptors 1/3 Largest family of cell-surface receptors (e.g. olfactoryreceptors) Seven-pass TM receptor proteins EC portion Cytoplasmic portion bound to trimeric G-protein  (α,β, subunits) 𝛄 video  G-Protein-Coupled Receptors 2/3  The target protein : (enzyme or ion channel)   700 GPCRs in humans 1/3of drugsthat are used worked through GPCRs  G-Protein-Coupled Receptors 3/3 When signal molecule This enzyme it will work is binding to GPCR it from activation of the will be disassociation alpha subunit and there GDP and GTP will bind and it will activate will be release of alpha subunit and this phosphate because the will lead to the affect protein have the intrinsic of activation GTPase activity =it could release or disassociate GDP or associate GTP Intrinsic GTPase according to the needs activity of the cells α-subunit switches itself off by hydrolyzing its GTP to GDP Video  Enzyme-Coupled Receptors Transmembrane proteins like GPCRs Intracellular domain: -acts as enzyme OR associated with enzyme inside the cell Largest class function as tyrosine protein kinases (called RTK) RTK : phosphorylates intracellular proteins on Tyrosine phosphorylate or will activate or will add phosphate group in the amino acid tyrosine why? To activate the receptor Catalytic domains are not attached > Signal molecule bind to receptor > catalytic domains are attached and activated or they activate an associated enzyme e.g. insulin, growth factors (VEGF, PDGF, EGF,…)  Why Signal Transduction is Important ? Glycogen breakdown in skeletal muscle these two types is very important for exams Gαs Gα s: stimulates adenylyl cyclase Gαi : inhibits adenylyl cyclase Glycogen breakdown in skeletal muscle is one of physiological reasons to fight or old year, from the book “fight or flight” response flight. It is break down of glycogen into of skeletal muscle glucose. First epinephrine ( adrenaline ) will bind to GPCR and it will be activated, adrenaline stimulates glycogen this will activate adenylyl cyclase , When breakdown in skeletal muscle these activated ,the complex will be cells. the hormone activates a activated and the ATP Adenylyl cyclase GPCR, which turns on a G protein (Gs) that activates adenylyl will activate in turn Gαs, which stimulates cyclase to boost the production of adenylyl cyclase. Once activated, adenylyl cyclic AMp. the increase in cyclic cyclase converts ATP into cyclic AMP AMP activates PKA, which (cAMP). Then cyclic AMP will activate phosphorylates and activates an PKA ( which was initially inactive. Then enzyme called phosphorylase it will activate phosphorylase kinase by kinase. this kinase activates adding phosphate. After that the in active glycogen phosphorylase, the glycogen phosphorylase will be activated enzyme that breaks down by adding phosphate , finally it will induce glycogen. Because these reactions do not involve changes the glycogen breakdown into glucose in gene transcription or new protein synthesis, they occur rapidly.  Why Signal Transduction is Important ? Rapamycin :macrolide antibiotic that is used to prevent organ transplantation rejection and also it used to treat some rare lung diseases Cell growth it could be also pathological it could be cancer or tumour and the rapamycin is used to inhibit the cell growth Rapamycin -  Rapamycin inhibits cell growth by induction of apoptosis on hepatocellular carcinoma cells in vitro. Why Signal Transduction is Important ? Diseases result from defective signaling pathways Drugs often target signaling mechanisms Poisons & pesticides often target signaling pathways Quiz (concept check)  Summary  Signal transduction : conversion of the signal from one form to another  Communication : receptor, target cell and large variety of EC signal molecules  Types of intercellular signaling : Endocrine, paracrine, Neuronal & contact- dependent  EC signal molecules bind either to cell-surface or intracellular receptors/enzymes  GPCRs activate G-proteins (switches) transmitting the signal then shut-off  Three main classes of cell-surface receptors: Ion-channel-coupled Receptors, GPCRs, Enzyme-coupled Receptors  GPCRs & enzyme-coupled receptors respond to signals by activating IC- signaling pathways.  TextbookReferences Email address: [email protected] Textbook References Essential Cell Biology 5th Edition; Chapter 16 Alberts raph text  1-All the following are considered as second 2- The extracellular signal is often converted into messengers EXCEPT: intracellular A. CyclicAMP signal which alter various mechanisms inside the cell. This B. Diacylglycerol process is? C. G protein A. Signaltransduction D. Inositol triphosphate B. Signal translation C. Signal transfusion 3- which of following is correct about Gαs A-stimulates adenylyl cyclase Question 1 and 2 from SC221 B-inhibits adenylyl cyclase 1-C 2-A 3-A  team Wishes you the best