Chapter 16 Cell Signaling

Chapter 16 Cell Signaling April 10 (W) April 12 (F) Cells need to sense and respond to their environment. Learning Outcomes explain the general principles of cell signaling  discuss how cells communicate signals and receptors define and understand signal transduction differentiate the 2 classes of...

Chapter 16 Cell Signaling April 10 (W) April 12 (F) Cells need to sense and respond to their environment. Learning Outcomes explain the general principles of cell signaling  discuss how cells communicate signals and receptors define and understand signal transduction differentiate the 2 classes of signaling molecules General Principles of Cell Signaling Information comes in a variety of forms. Communication involves converting information signals from one form to another. This process of conversion is called signal transduction. Signal transduction is the process of converting one type of signal into another. A target cell converts an extracellular signal into an intracellular signal. Essential Cell Biology, Fifth Edition Copyright © 2019 W. W. Norton & Company Signals can act over long or short range Examples of extracellular molecules used as signals: proteins, peptides, amino acids, nucleotides, steroids, fatty acid derivatives and gases Endocrine Signaling-coming long distance in from endocrine Cells Lex : hormones it is being general paracrine-hormones signaling molecules ; local mediator , only received by neighboring Cells What are the means on how cells communicate and thus relay the information across from one cell to the other? Autocrine Signaling-signal Synaptic released Signaling-long distance but the target is specific , Contact dependent-membrane bound signal molecule , signal is neurotransmitter not released , target cell has to be very close to each other Secreted Cells Have 4 Basic Styles of Communication Some Facts on Cell Signaling Each cell responds to a limited set of signals. Different types of cells respond to the same signal in different ways. signal- neurotransmitteracetylcholine Same Signal, but the Responses are in Different Ways Same signal but the responses are in different ways These are brought about by different: 1. mediator molecules inside the cell 2. receptor molecules on the cell membrane A Cell Depends On Multiple Extracellular Signals The signal molecules work in combinations to regulate the behavior of the cell. Receptors Relay Signals via Intracellular Signaling Signal’s target is a receptor protein. Each receptor is signal specific. Receptor performs the primary transduction step which is receiving the signal and then generating a new intracellular signal –the first event in the chain of intracellular signal transduction pathway A Cell’s Response to a Signal Can Be Fast or Slow Classes of Extracellular Signals (A) those that bind to cell surface receptors and activate intracellular enzymes (B) those that bind to intracellular receptors that regulate gene expression large hydrophilic Some Hormones Cross the Plasma Membrane and Bind to Intracellular Receptors Hormones are chemicals that coordinate different functions in your body by carrying messages through your blood to your organs, skin, muscles and other tissues. These signals tell your body what to do and when to do it. Steroid receptors are dimers of zinc-finger proteins that reside within the nucleus except for the glucocorticoid receptor which resides in the cytosol until it binds its ligand. Hormone receptors are capable of regulating gene transcription. Some Dissolved Gases Cross the Plasma Membrane and Activate Intracellular Enzymes Directly Nitric oxide crosses plasma membrane and activates intracellular enzyme directly. Nitric oxide crosses plasma membrane and activates intracellular enzyme directly NO binds to guanylyl cyclase = formation of cyclic GMP  Cyclic GMP the intracellular signal that activates a signaling cascade of events leading to a cell’s ultimate response Increase in cyclic GMP Muscles = relax, allows the vessel to dilate so that blood flow through it more freely Nitric oxide crosses plasma membrane and activates intracellular enzyme directly Example: Viagra enhances penile erection by blocking degradation of cyclic GMP prolonging NO signal. Clinical application Nitroglycerin will dilate veins more than arteries, decreasing cardiac preload and leading to the following therapeutic effects during episodes of angina pectoris (chest pain due to lack of oxygen) GENERAL PRINCIPLES OF CELL SIGNALING Signals Can Act over a Long or Short Range Each Cell Responds to a Limited Set of Signals A Cell’s Response to a Signal Can Be Fast or Slow GENERAL PRINCIPLES OF CELL SIGNALING Some Hormones Cross the Plasma Membrane and Bind to Intracellular Receptors Some Dissolved Gases Cross the Plasma Membrane and Activate Intracellular Enzymes Directly The Functions of Proteins in the Signaling Cascade https://www.youtube.c om/watch?v=qOVkedx DqQo Intracellular Signals Examples of intracellular signaling molecules: small molecules- cyclic GMP, cyclic AMP, Ca2+, proteins Many intracellular signaling proteins act as molecular switches- receipt of a signal switches them from an inactive state to an active state Two Main Classes of Molecular Switches GTPase activity GTP-Binding Proteins  hydrolyze their bound GTP to GDP, using their own intrinsic GTPase activity. Examples: (1) trimeric GTP-binding proteins (2) monomeric GTP-binding proteins GAP- GTPase activating proteins GEF- guanine nucleotide exchange factor GENERAL PRINCIPLES OF CELL SIGNALING Cell-Surface Receptors Relay Extracellular Signals via Intracellular Signaling Pathways Some Intracellular Signaling Proteins Act as Molecular Switches Phosphorylation and Dephosphorylation GTP-GDP Exchange Learning Outcomes Understand and explain mechanisms on how G-coupled receptors facilitate intracellular cell signaling Differentiate PKA, PKC and CaM K Cell-Surface Receptors Fall into Three Main Classes (1) Ion-Channel–Coupled Receptors Convert Chemical Signals into Electrical Ones 1. (2) G-Protein–Coupled Receptors- activate 2.G-proteins; G-Protein-Coupled Receptors G-proteins then activate enzymes or ion channel receptors Figure 16-15b Essential Cell Biology (© Garland Science 2010) (3) Enzyme Coupled Receptors- have intrinsic enzyme activity or they associate 3.with Enzyme-Coupled Receptors enzymes Figure 16-15c Essential Cell Biology (© Garland Science 2010) Morphine, Heroin Endorphins, Enkephalins Analgesia, Euphoria G-protein linked receptors Mediate responses to diverse extracellular signals—hormones, local mediators, neurotransmitters single polypeptide, seven-pass transmembrane receptor protein These are the largest family of cell surface receptors, but all G-protein linked receptors have the same structure. Stimulation of GPCRs Activates G-Protein Subunits 3 subunits Let’s discuss: How does GPCR activate G-proteins? Stimulation of GPCRs Activates G-Protein Subunits G-protein linked receptors: proceeding further Cholera toxin acts on the Gprotein. If G-protein is always on, the flow of Cland water into the gut lumen is continuous—resulting into diarrhea and dehydration. G-protein α-subunit switches itself off by hydrolyzing its bound GTP What is the implication if the G-protein is kept on all the time? Some G Proteins Directly Regulate Ion Channels slowing heart beat G-PROTEIN-COUPLED RECEPTORS Stimulation of GPCRs Activates G-Protein Subunits Some Bacterial Toxins Cause Disease by Altering the Activity of G Proteins Some G Proteins Directly Regulate Ion Channels Many G Proteins Activate Membrane-bound Enzymes that Produce Small Messenger Molecules The Cyclic AMP Signaling Pathway Can Activate Enzymes and Turn On Genes Some G Proteins Activate Membranebound Enzymes Most frequent target enzymes:  adenylyl cyclase  phospholipase C HOW does PKA get activated by cyclic AMP? Adenylyl cyclase synthesizes cAMP cAMP phosphodiesterase degrades cAMP Figure 16-21 Essential Cell Biology (© Garland Science 2010) Fluorescence and cAMP -fluorescence protein that respond to cAMP cAMP affects quite a number of proteins in a signaling cascade, the cells’ ultimate responses will be varied. Cyclic AMP pathway: Many intracellular signals acting via G-protein-linked receptors affect the activity of adenylyl cyclase, then … Protein Kinase Aphosphorylates The Cyclic AMP Pathway Can Activate Enzymes and Turn On Genes a rise in intracellular cyclic AMP can activate gene transcription Receipt of extracellular signals can change cell behavior quickly (e.g., in seconds or less) or much more slowly (e.g., in hours). A. What kind of molecular changes could cause quick changes in cell behaviour? B. What kind of molecular changes could cause slow changes in cell behaviour? Second Messengers Inside the Cell The original signal usually doesn't enter the cell. The small molecule "cAMP" was the initial second messenger to be identified. Other examples of second messengers include NO (nitric oxide), IP3 (inositol 1,4,5-triphosphate), and DAG (diacylglycerol). Some G Proteins Activate Membranebound Enzymes Most frequent target enzymes:  adenylyl cyclase  phospholipase C The Inositol Phospholipid Pathway Triggers a Rise in Intracellular Ca2+ Rise in Intracellular Ca2+ Triggers Many Biological Processes Starfish egg was injected with a Ca2+ sensitive dye. Figure 16-26 Essential Cell Biology (© Garland Science 2010) When a sperm enters an egg- release of Ca2+ from ER lumen increasing cytosolic Ca2+- provokes a change in the egg surface, preventing entry of other sperm A Ca2+ Signal Triggers Many Biological Processes Figure 16-27 Essential Cell Biology (© Garland Science 2010) Ca2+ binds to calmodulin and the Ca2+-calmodulin complex activates CaMkinase Ca2+ binds Conformational change Wrapping around the target protein Activity of target protein altered Effects of Ca2+ are Indirect Effects of Ca2+are mediated through interaction of Ca2+ with transducer proteins known as Ca2+ binding proteins Most common is calmodulin Ca2+/calmodulin-dependent protein kinases (CaM-K) Important in neuronal activity Mutant mice that lack the CaM kinase showed marked inability to remember. G-PROTEIN-COUPLED RECEPTORS The Inositol Phospholipid Pathway Triggers a Rise in Intracellular Ca2+ A Ca2+ Signal Triggers Many Biological Processes G-PROTEIN-COUPLED RECEPTORS Protein kinases are proteins involved in the signaling cascades PKA, protein kinase A activated by cyclic AMP PKC, protein kinase C activated by Ca2+ CaM K, kinase activated by activated Ca2+ bound calmodulin