Cell Signaling Supplementary Slides PDF

BIOL1025 Fundamentals of Cell Biology and Physiology Signalling pathways induced in cells Supplementary slides Dr Charles Birts email: [email protected]  Gases Produced by specific enzymatic pathways. Highly so...

BIOL1025 Fundamentals of Cell Biology and Physiology Signalling pathways induced in cells Supplementary slides Dr Charles Birts email: [email protected]  Gases Produced by specific enzymatic pathways. Highly soluble in water and lipids – so can cross plasma membrane. Cant be stored thus needs to be produced on demand. Produces local (paracrine/autocrine) effects. Generally cause vasodilation and may have immunological effects. CO CO2 Carbon monoxide Carbon dioxide Nitric oxide H2S NO Hydrogen sulfide Nucleic Acids The purinergic nucleotides ATP/ADP and their nucleoside adenosine function as paracrine signalling molecules. They have specific cell surface receptors (G protein associated). During cellular stress (e.g. ischemia /reperfusion or inflammation), multiple cell types release ATP into the extracellular space. Induce vasodilation, neural effects (in development), innate immune changes e.g. inflammatory cytokine release, fever. Fatty acid derivatives Platelet activating factors (PAFs) and Eicosanoids e.g. prostaglandins, thromboxanes, leukotrienes. Paracrine signals (sometimes hormones - pregnancy) Produced through modification and release of lipids in the plasma membrane Eicosanoids – arachidonic acid Platelet activating factor-phosphorylcholines Polar so don’t rapidly cross cell membrane - have receptors on the plasma membranes. Regulate immune responses, inflammation (vascular permeability), pain reactions, vasoconstriction/ dilation and clotting. Cholesterol derivatives (steroids) Hormones - transported by the circulatory system to target distant organs: - Sex (gonadal/ placental) steroids: Oestrogens, Progesterones, Testosterone. - Adrenal steroids: Mineralocorticoids (aldosterone) Glucocorticoids (cortisol) - Vitamin D! Produced on demand – can’t be stored. Not very water soluble so may have a carrier in the plasma e.g. albumin. Readily crosses the cell membrane – main receptors inside the cell not at the membrane. Amino acids and derivatives All are released by exocytosis and are relatively lipid insoluble, they are not going to cross the plasma membrane. Amino acids - neurotransmitters (paracrine) - stored in intracellular vesicles until they are needed e.g. Glutamate, Aspartate: excitatory Glycine: inhibitory Amino Acid derivatives - active (biogenic) amines, produced by decarboxylation of amino acids. - Histamine from histidine (paracrine) Immune responses, vasodilation, acid secretion in GI tract, neurotransmitter. - GABA (γ-aminobutyric acid) from glutamate (paracrine) Inhibitory neurotransmitter. - Serotonin from tryptophan Neurotransmitter, vasodilation. Amino acids and derivatives Amino Acid derivatives continued… Catecholamines produced after tyrosine decarboxylation - Dopamine: neurotransmitter - Noradrenaline: neurotransmitter - Adrenaline: hormone, neurotransmitter modification Important to know: They are all modified biogenic amines. Other tyrosine modifications: - Conjugated/ iodinated thyroid hormones Peptides and Proteins Largest class of signalling molecules. Ranges in size from 3 amino acids e.g. TRH = Glu-His-Pro-(N) to growth hormone e.g. GH ~200 amino acids. Lipophobic - not going to cross the cell membrane, so they can be stored with in the cell. need to bind a receptor on the cell surface of the target cell. Thyrotropin-releasing hormone (TRH) human growth hormone (GH)  BIOL1025 Fundamentals of Cell Biology and Physiology Signalling pathways induced in cells Lecture 1 Dr Charles Birts MyEngagement: email: [email protected] Signalling pathways induced in cells Two lectures: Lecture 1: How to define a cell signal. Lectures 2: Receptors and Signal transduction. Learning outcomes: LO1 - explain why cells need to communicate and to give examples of some of the processes involved in animals. LO2 - define and distinguish the roles of membrane bound, secreted and diffusible signalling molecules and relate this to their functions. Useful texts… Essential Cell Biology 5th International Student Edition Chapter 16 Human Physiology: An Integrated Approach 8th Edition Chapter 6 Summary Videos in Jove Ways of defining a cell signal 3 1: What type of signal? also to monitor its intracellular extracellular environment thermoreceptors. - and CLigand) - Mechanical or (Bio)chemical or other - light receptors proteins that produce ↳ e touch musche cells Regulatory sent from g which are chemical signals.. , e in the body, or place to another proteins (receptor one cell- other within the 2: What form of signal? that respond recognize to the them. signals and -Separation of signalling cell and receiving cell 3: What is the molecular form of the signal molecule? 4: What form of receptor and events are triggered in the cell?  (Bio)chemical signalling This is the main topic for this lecture, this course and your degree – Biomedicine/ Pharmacology/ Biochemistry and Neuroscience. For biochemical signals we need a ligand and a receptor. A signal ligand is a small molecule that forms a complex with a macromolecule typically a receptor protein that results in a conformational change in the receptor that then generates a signal. what kind of Ligand? Where it ? is Pligante binds to a very specific causes receptor and a conformational change. ( what communication between kind ? sells in multicellular mediated organism is mainly by extracellular molecules Signal , Ways of defining a cell signal 1: What type of signal? - Mechanical or (Bio)chemical or other 2: What form of signal? -Separation of signalling cell and receiving cell 3: What is the molecular form of the signal molecule? 4: What form of receptor and events are triggered in the cell? Forms of signal- Where is the signal released from? Contact-dependent signals (Juxtacrine): signals target adjacent touching cells (more details in later lecture). I have to be touching- protein-Protein - interaction Cell- Matrix signals – signals from the insoluble extracellular matrix -Protein- or Lipid (more details in later lecture). Protem- sugar Soluble signals - Autocrine (intracrine), Paracrine and Endocrine. interaction. Membrane bound signal molecule Signalling cell Target cell  immune Contact-dependent signals and in - important during development system responses. (Juxtacrine): Require interaction between membrane molecules on two cells. Cells must be touching. Signals are transmitted through cell membranes via protein or lipid components integral to the membrane of the emitting cells e.g. Delta – Notch (later lecture). Membrane bound signal molecule receptor notch - Signalling cell Target I cell Ligana  Forms of signal- Where is the signal released from? Contact-dependent signals (Juxtacrine): signals target adjacent touching outside cells (more details in later lecture). maintains environment cell Cell- Matrix signals – signals from the insoluble extracellular >half - matrix of (more details in later lecture). ! body made up of this. Soluble signals - Autocrine (intracrine), Paracrine and Endocrine. Involve interactions with the cell extracellular matrix impacting based on the matrix's behaviour and Structure. composition cells secrete Signalling molecules into Signals fluid. extracellular mediates the I ↑ integrin : receptors Forms of signal- Where is the signal released from? Contact-dependent signals (Juxtacrine): signals target adjacent touching cells (more details in later lecture). Cell- Matrix signals – signals from the insoluble extracellular matrix (more details in later lecture). Soluble signals - Autocrine (intracrine), Paracrine and Endocrine. paracrine Autocrine # cell and - signalling targetting cell intracrine well are the same ~ use - ci rcul a tory as L Endocrine Autocrine signals - e. g. Cancer proliferation. cells, they produce extracellular signals that stimulate their own survival and Autocrine signals are secreted, and affect the target cell itself via its own receptors. - produces & signalling ligand and put it on itself to transduce a it and cause itself responseon Examples: /IL1 1 - Interleukin- 1 a cytokine released by macrophages. Effects neighbouring cells and the secreting cell “activating them”. 2 - Interleukin-2 is released by T lymphocytes on meeting an antigen and causes them to proliferate. 412 Intracrine signals Intracrine signals -produced by and stay within target cells (a version of autocrine signaling). Often overlooked but steroid hormones have their receptors in the cell so can act as intracrine (and paracrine and endocrine signals) itself can target and other neighbouring weby a format it. releasing  are oncels c te local environment Paracrine signals - setreemolecules that only act Paracrine signals target cells in the vicinity of the emitting cell. Examples: immune cells; Neurotransmitters at synapses. Local mediators released into the interstitial fluid include: Histamine, TGFβ, Growth factors, Cytokines. S - are to close the other bute cass contact. Chemical Synapses - Neuronal Signals are itisresed paracrine signals Endocrine signals > secrete their ↳ signal molecules called - e hormones. g. neurons - extend long ayons that contact target cells far away. Endocrine signals target distant cells by producing hormones that travel through the circulation to reach all parts of the body. Many examples including adrenalin and thyroid stimulating hormone. and - have Specific correct make ligand receptors. it into Release reach blood to its target cen a and cause withou response it Endocrine signals are very low, Hormones are at low concentrations in the blood/ interstitial fluid e.g Thyroxine 0.09-20 pg/ml Oestrodiol 1 pg = 1 x 10-12 g 20-400 pg/ml Prolactin 3-15 ng/ml Far lower levels (pM) than the local concentration of ligands used in paracrine, cell-matrix and cell-cell signals. Hormone receptor binding has usually far greater affinity (low -the lower thekd the Kd) compared to the others. stronger the Hormone receptors are part of allinity of interaction amplification cascades.. the signal to be - needs low concentration amplified as - may not cause a strong response as needed. Ways of defining a cell signal 1: What type of signal? - Mechanical or (Bio)chemical or other 2: What form of signal? -Separation of signalling cell and receiving cell 3: What is the molecular form of the signal molecule? 4: What form of receptor and events are triggered in the cell?  molecules are released Chemical Classification of External These signalling exocytosis into the extracellular space by just Messengers Signalling molecules from signalling the diffase through cells the bilayer. , some for the cell surface Gases: NO, CO, H2S, CO2. stay receptor contact some on call 's to come un other S Nucleic Acids: ATP, ADP and adenosine. when these Fatty acid derivatives: Eicosanoid e.g. prostaglandins, thromboxanes, Nucleic arids leukotrienes, PAFs. areseages Cholesterol derivatives: steroids readily available easy to store and make and extracelarlag - easy to , than Amino acids and derivatives: glycine, glutamate, thyroid hormones, modify. it acts catecholamines- e.g. adrenaline as signaling Peptides: e.g. TRH made from 3 peptides - molecule Proteins: e.g. Insulin. See supplementary notes in Blackboard for more details different effects different types of unslecule often has on a signal to differences in the intracellular signalling proteins, target cells. This is due activated. that are elector proteins and genes Ways of defining a cell signal 1: What type of signal? - Mechanical or (Bio)chemical or other 2: What form of signal? -Separation of signalling cell and receiving cell 3: What is the molecular form of the signal molecule? 4: What form of receptor and events are triggered in the cell?  Form of receptor and events triggered in the cell The form of the signal molecule decides the position of the receptor: Lipophilic (hydrophobic) molecules - e.g. Steroids (cortisol) and Gases (NO). - Can enter the cells so the receptors can be anywhere, often within the the ligand has i to enter the cell cytosol. or cytoplasm as receptor can pass through the hydrophobic to hind to them: this bilayer easily. requires that the Hydrophilic molecules cannot diffuse across the can signal molecule - bilayer be sudiciently small - e.g. Amines (serotonin), Amino Acids (Glycine), Peptides (ACTH) and becomeactivatedanda and hydrophobic to dillage across Proteins (Insulin). D wen bingand, receptor ofthe. cell the target cell's Plasma membrane. - Can’t cross the plasma membrane so receptors at the cell surface. Exception - Rule breaker butcan diffuse across the bilayer. ~ ↓ by using transporter proteins. * Thyroid hormones – are Hydrophobic but have · a carrier at the cell surface to bring the ligand into the cell and have receptors in the cytoplasm.. cell then initiates a response in the target Receptor binds Ligand to , sheut -Thebondingsitesofthepanasampestuurthats not the many other to only to a appropriate signal and the receptor responds molecules the cell is exposed to signaling Target cell receptors may be on the cell surface or inside the cell Lipophilic signaling Hydrophilic signaling  Eachcellprogrammedtoresponda ar Signals. to Ligands by only Thewell only responds selectively , and intracellular those receptors transtruction expressing only to the signals that are chemical. signalling required systems for the that responds regulation of that call. Signal transduction Defined as: How chemical or physical signals are transmitted through a cell as a series of molecular events. - - The changes elicited by ligand binding to a receptor give rise to a signalling cascade, a chain of biochemical events - a signalling pathway. Lalso amplify response. all signalling patways interact with each other ↳ Signalling pathways may interact with one another to form networks, which allow coordinated cellular responses: Interseeing changes in the transcription or translation of genes. with each ther post-translational and conformational changes in proteins. &. changes in protein location. changes in ion concentration. Signal transduction can alter cell growth, proliferation, metabolism, movement, secretion and many other processes.  the transduction signal withh Messengers is released Ligand that from signalling First messengers: signaling molecules C el. (hormones/ paracrine/ autocrine agents) that reach the cell from the extracellular Receptor fluid and bind to their specific receptors. tot Signaling ligand will have messenger but only end some may need messenger Second messengers: substances that relays message from the plasma membrane to the cytoplasm to trigger a response. receptor to activation and ↳ are generated in large amounts in response to parts of the cell They from their spreading the signal other. diffuse away source, to and altering the behavior of siected Signalling pass the signal on by binding or elector proteins. Cell surface receptors need second messengers. Second messengers Turning off the signals Has major bearing on the length (?strength) of effects and in paracrine signals the field of influence. ↳ the acheet a signal should be turned on of the response. as well as turn off. 1. Spontaneous breakdown - e.g. NO is very labile (a free radicle with an unpaired electron) and is - converted to NO3- quickly and needs no catabolising enzyme. - Hence it cant move far from its site of production and has very local effects. - has limited effect and is Nitric oxide NO3- localised -only alleat some signathing pathways. cannoteffect endocrine us - it is not localised. Turning off the signals 2. Enzymatic breakdown - cleavage of signal molecule to (in)active components. off turns signal rapidly very. - e.g. Acetyl Cholinesterase breaks down acetylcholine at the synapse. The enzyme is at high concentration (mostly membrane bound) and so there is only very local effect at the synapse which is short acting. - e.g. Proteases cleave peptide/ protein hormones (insulin, glucagon etc), these are often at lower concentrations and so produce longer term effects. - Insulin - & ↑ Turning off the signals goes back thecel that Formed it. 3. Reuptake to - - Many neurotransmitters are transferred back into the secreting cell – e.g. GABA, glycine, serotonin. 4. Receptor/ Ligand Internalisation - Some ligands and their receptor are brought into the cell following binding ans – e.g. somatostatin and Luteinizing hormone. a broken down by cosozymes.  Breakdown/ uptake pathways are targets for pharmaceutical agents Neostigmine: blocks acetylcholine esterase and so increases the Seffectiveness of acetylcholine – used to to treat myasthenia gravis. reduce its stop break down of acetylcholine. function-t Fluoxetine (Prozac): blocks serotonin uptake at the synapse - used to treat depression as the ligand is retained at the synapse for longer. ↳ o serotonin can be released and create response more unk not taken back. cell by the signalling Cell Signalling and Receptors Learning outcomes: LO1 - explain why cells need to communicate and to give examples of some of the processes involved in animals. LO2 - define and distinguish the roles of membrane bound, secreted and diffusible signaling molecules and relate this to their functions. Useful texts… Essential Cell Biology 5th Ed Human Physiology: Chapter 16 An Integrated Approach 8th Ed Chapter 6 Questions to answer about any signalling molecule: What cell produces it? Why is it released? What form of molecule is it? How is it carried to its receptors? Where is its receptor on the cell? What cells carry the receptor? What pathways does ligand receptor binding induce? What effects are caused by signalling? How are the signals stopped? What happens if too much signal or too little signal is released?  1. What cell produces it? The cell type producing a signaling molecule varies depending on the molecule’s function. For instance, immune cells like macrophages produce cytokines, while endocrine cells like those in the pancreas produce hormones such as insulin. 2. Why is it released? Signaling molecules are released to relay important messages and coordinate activities between cells. This can include responses to external stimuli (like infection or stress), regulatory processes (such as growth or metabolism), or communication between neurons in the brain. 3. What form of molecule is it? Signaling molecules can take various forms: Gases (e.g., nitric oxide) Steroids (cholesterol derivatives) Peptides and Proteins (e.g., insulin) Amino acids or their derivatives (e.g., adrenaline) Nucleic acids (e.g., ATP) 4. How is it carried to its receptors? The transport mechanism depends on the signal type: Endocrine signals travel through the bloodstream to distant targets. Paracrine signals diffuse through interstitial fluid to nearby cells. Autocrine and intracrine signals act on the same cell that produces them. Juxtacrine signals require direct cell-to-cell contact. 5. Where is its receptor on the cell? Receptor location depends on the signal’s properties: Hydrophobic molecules like steroids can cross the cell membrane, so their receptors are often intracellular. Hydrophilic molecules (e.g., proteins or peptides) cannot cross the membrane, so they bind to receptors on the cell surface..  6. What cells carry the receptor? The presence of receptors varies by cell type and function: For example, muscle and liver cells have insulin receptors, while immune cells carry receptors for cytokines. Target cells for a hormone or neurotransmitter must express the appropriate receptors to respond to the signal. 7. What pathways does ligand-receptor binding induce? Ligand binding typically initiates a signal transduction cascade within the cell, which may include: Activation of second messengers (like cAMP or calcium ions). Protein phosphorylation events leading to changes in cellular activities. Gene expression modulation if the signal affects transcription factors. 8. What effects are caused by signaling? The effects vary widely but can include: Changes in gene expression Protein modification or relocation Cell growth, movement, or differentiation Alterations in metabolism or ion balance 9. How are the signals stopped? Signals are terminated through several mechanisms: Enzymatic breakdown of the signaling molecule (e.g., acetylcholinesterase breaks down acetylcholine). Receptor internalization and degradation. Reuptake of neurotransmitters into the originating cell. 10. What happens if too much signal or too little signal is released? Imbalances in signaling can cause diseases: Excessive signaling may lead to conditions like cancer (due to overactive growth signals) or overstimulation of the nervous system. Insufficient signaling can cause issues like diabetes (inadequate insulin signaling) or depression (low neurotransmitter activity).