Bio121_F24_Cellular Communication_Student (2) PDF

Cell Signaling Campbell Biology Sections 11.1-11.4 Professor Andrea Greiff Biology 121 – Cell Biology 1 Objectives: We will build on what we know of membrane structure and transport acr...

Cell Signaling Campbell Biology Sections 11.1-11.4 Professor Andrea Greiff Biology 121 – Cell Biology 1 Objectives: We will build on what we know of membrane structure and transport across membranes to learn how extracellular signals get transmitted across the plasma membrane These signals allow the cell to sense its environment and respond accordingly Responses may involve gene expression (nucleus, ribosomes, DNA, RNA, protein), release of calcium stored in the ER, opening/closing of membrane transport proteins, etc. 2  Cells Can Signal Over Large and Small Distances Signal molecules are classified by the distance they travel to their site of action Endocrine signals are produced far from their site of action and carried by the bloodstream to their target Paracrine signals are produced and act locally Juxtacrine signals require physical contact between sending and receiving cells Autocrine signals are produced by the same cell reacting to them https://www.nature.com/articles/cddis2016336 3 Question 1 Match the signal type to its distance traveled Signal types Distance traveled Endocrine Local signaling between cells Paracrine Signal sent and received by the same cell Juxtacrine Signal sent, received by adjacent cell Autocrine Long distance signaling – usually carried by the bloodstream to its target 4  Basic Steps in Cell Signaling Cell-surface receptors Intracellular Receptors 1) Ligand Binding (Signal Reception) Intracellular 2) Signal Transduction receptors translocate to the nucleus rather than initiating a signaling cascade 3) Cellular Response 5  First Step: Receptors and Ligands Ligand: a messenger molecule that binds receptors either on the cell surface or intracellularly Hydrophilic ligands bind cell surface receptors Hydrophobic ligands bind cytosolic receptors Review: why would hydrophilic ligands bind cell surface receptors and hydrophobic ligands bind cytosolic receptors? 6 https://www.khanacademy.org/science/biology/cell-signaling/mechanisms-of-cell-signaling/a/signal-perception  Cell Surface Receptors vs. Intracellular Receptors Intracellular receptor Cell surface receptor Binds: hydrophilic ligands Binds: hydrophobic ligands and small molecules General Classes: Found in the cytoplasm and nucleus G Protein Coupled Receptors Kinase Receptors Ligand-Gated Ion Channels 7  Step Two: Signal Transduction Transmission of a signal from a cell surface receptor to its target often involves a phosphorylation cascade Phosphorylation usually activates a messenger Kinases are enzymes that transfer phosphate groups proteins Some receptors have kinase activity of their own to start this process Receptor Tyrosine Kinases (RTKs) https://www.researchgate.net/figure/304629022_fig1_Figure1-protein- phosphorylation-and-dephosphorylation-Protein-phosphorylation-was 8  Amplification of Signal A phosphorylation cascade involves many molecules phosphorylating each other to transmit the signal Each step of the cascade yields multiple phosphorylated products, so the input of one signal is amplified many times over Think about it like throwing a stone in a pool of water – the one stone makes many ripples that get bigger as they move away 9  Step 3: Response The cell’s response to a signal depends on the cell type and signal received May be a single response or multiple responses Examples of responses: Regulation of gene expression: turning on or off the expression of a gene Regulation of a protein: activation or inactivation Rearranging the cytoskeleton https://en.wikipedia.org/wiki/Insulin_signal_transduction_pathway 10  After the Response… Cells need to be able to stop responding to a signal The messengers were activated by kinases that covalently attached a phosphate group to them That activation cannot just “fall off” Phosphatase enzymes remove phosphate groups to inactivate messengers Messengers can then be reused https://www.researchgate.net/figure/304629022_fig1_Figure1-protein- phosphorylation-and-dephosphorylation-Protein-phosphorylation-was 11  Shutting Down the Cascade Phosphatase activity 12 Question 2 Put the basic steps of cell signaling in order: Signal transduction Turn off signal Ligand binds receptor Response 13  Second Messengers Not all players in signal transduction are phosphorylated proteins First messenger: signaling molecule (ligand) Second messenger: small DAG molecules produced in response to the first messenger PIs Second messengers can diffuse through the cell to transmit signals https://www.slideshare.net/Ariane27/second-messenger-camp-pathway 14  G Protein-Coupled Receptors (GPCRs) GPCRs are cell surface receptors that work together with G proteins to transmit signals Transmit signals via various second messengers Diverse group of receptors: almost 1000 different GPCRs in humans GPCR GPCRs are transmembrane (integral) proteins G proteins are lipid-anchored membrane proteins Inactive when GDP is bound Active when GTP is bound Remember: GPCRs and G proteins are two different things G Protein Review: what type of membrane protein is a GPCR? G protein? 15  Ligand Binding to GPCR Causes G Protein Activation When a ligand binds to a GPCR, the GPCR changes shape This shape change allows the GPCR to GPCR bind a G protein Binding of the GPCR to G protein causes the G protein to release GDP and bind GTP G Protein Binding of GTP activates the G protein 16  Activated G Proteins Initiate Signal Transduction Once a G protein is activated by GTP, it goes on to activate (or inhibit) other proteins in order to transmit the signal initiated by ligand binding to GPCR 17 GPCRs and Cyclic AMP (cAMP) Many GPCRs produce cAMP as a second messenger 1. Ligand binding to GPCR activates G protein 2. Activated G protein activates adenylyl cyclase 3. Adenylyl cyclase converts ATP to cAMP 4. The main target of cAMP is protein kinase A (PKA) PKA goes on to phosphorylate cellular proteins Draw this process out with your group 18  cAMP as a Second Messenger cAMP is produced as a second messenger to transmit signals received by GPCRs cAMP cAMP then activates a kinase (PKA) to perpetuate the signal Increasing cAMP concentrations have many possible effects: In skeletal muscle and liver cells: breakdown of glycogen In cardiac muscle: strengthens contractions In intestinal epithelium: secretion of salt and water Video: GPCRs and cAMP 19 GPCR Signaling Cascade Ligand binding – signal reception G protein activated Active G protein activates another protein (adenylyl cyclase) Second messenger (cAMP) produced Phosphorylation cascade Cellular response 20  Hydrolysis of GTP Inactivates G Protein G proteins “turn themselves off” by hydrolyzing their GTP to GDP using their own phosphatase 21 Question 3 What are the first and second messengers in this signaling pathway? 22  GPCRs and Calcium ions (Ca2+) Ca2+ is another second messenger that transmits signals received by GPCRs Normally, intracellular levels of Ca2+ are much lower than extracellular levels ER and mitochondrial membranes contain Ca2+ pumps to store Ca2+ within the organelle Increasing the intracellular Ca2+ concentration by releasing it from ER, mitochondria leads to cellular responses 23  GPCRs and Ca2+ Binding of a ligand to its GPCR causes activation of G protein The activated G protein activates the enzyme, phospholipase C (PLC) PLC cleaves PIP2, a membrane phospholipid, into diacylglycerol (DAG) and inositol triphosphate (IP3) DAG remains attached to the membrane IP3 is released as a diffusible second messenger 24  GPCRs and Ca2+ IP3 is soluble allowing it to diffuse through the cytosol to IP3-gated Ca2+ channels on the ER IP3-gated Ca2+ channels are an example of a ligand-gated ion channel IP3 binding to the channel opens it allowing Ca2+ to diffuse into the cytosol Think of IP3 as the key that opens Ca2+ gates 25  GPCRs and Ca2+ Release of Ca2+ from the ER into the cytosol causes the activation of numerous proteins These activated proteins go on to elicit cellular responses Draw out this process with your group Video: Calcium and IP3 26 Question 4 Which of these puts the events of GPCR-related signaling in order? a) First messenger binds GPCR à G protein “docks” with GPCR à G protein exchanges GDP for GTP, becomes activated à G protein activates production of a second messenger à response b) First messenger binds GPCR à G protein exchanges GDP for GTP, becomes activated à G protein “docks” with GPCR à response à G protein activates production of a second messenger c) First messenger binds GPCR à G protein activates production of a second messenger à G protein exchanges GDP for GTP, becomes activated à G protein “docks” with GPCR à response 27  Stopping Cell Signaling Receptor-ligand interactions are reversible Usually, a certain amount of receptor-ligand complexes must be made before the signal is transmitted A signal is commonly initiated by a change in the concentration of ligand Reducing the number of ligand molecules available stops signaling Receptor desensitization occurs when receptors bind too much ligand for long periods causing cells to no longer respond to signals Cells adapt to the constant signaling by reducing the number of receptors available or changing the receptors so they are not as sensitive to ligand Ligand concentration has to increase even further to cause the cell to respond Cells can return to previous levels of sensitivity once ligand levels drop to “normal” 28