Transcript receptor
Warm-Up 1. Why do you communicate? 2. How do you communicate? 3. How do you think cells communicate? 4. Do you think bacteria can communicate? Explain. 5. Compare the structure & function of these receptor proteins: GPCR, tyrosine kinase and ligand-gated ion channels. 6. What is a second messenger? What are some examples of these molecules? 7. What are the possible responses to signal transduction in a cell? Cell Communication Ch 11 What you should know: The 3 stages of cell communication: reception, transduction, and response. How G-protein-coupled receptors receive signals and start transduction. How receptor tyrosine kinase receive cell signals and start transduction. How a cell signal is amplified by a phosphorylation cascade. How a cell response in the nucleus turns on genes while in the cytoplasm it activates enzymes. What apoptosis means and why it is important to normal functioning of multicellular organisms. External signals are converted into responses within the cell What does a “talking” cell say to a “listening” cell, and how does the latter cell respond to the message? Microbes are a window on the role of cell signaling in the evolution of life One topic of cell “conversation” is sex. An example would be yeast (used for making beer, wine, and bread). Yeast cells identify their mates by chemical signaling. Communication between mating yeast cells 1. 2. 3. Exchange of mating factors- Each cell type secretes a mating factor that binds to receptors on the other cell type Mating- Binding of the factors to receptors induces changes in the cells that lead to their fusion New cell- The nucleus is a fused cell that includes all the genes from the original cells Exchange of mating factors a factor Receptor a a Yeast cell, a factor mating type a Yeast cell, mating type a Mating a a New a/a cell a/a Evolution of Cell Signaling A signal-transduction pathway is a series of steps by which a signal on a cell’s surface is converted into a specific cellular response Signal transduction pathways convert signals on a cell’s surface into cellular responses Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and have since been adopted by eukaryotes Local and Long-Distance Signaling Cells in a multicellular organisms communicate by chemical messengers Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells In local signaling, animal cells may communicate by direct contact In many other cases, animal cells communicate using local regulators, messenger molecules that travel only short distances In long-distance signaling, plants and animals use chemicals called hormones Cell Signaling Animal cells communicate by: Direct contact (gap junctions) Secreting local regulators (growth factors, neurotransmitters) Long distance (hormones) Plasma membranes Communication by direct contact between cells (a) Cell JunctionsBoth animals and plants have cell junctions that allow molecules to pass readily between adjacent cells without crossing plasma membranes. (b) Cell-Cell recognition- Two cells in an animal may communicate by interaction between molecules protruding from their surfaces. Gap junctions between animal cells Cell junctions Cell-cell recognition Plasmodesmata between plant cells Local signaling Long-distance signaling Target cell Secreting cell Local regulator diffuses through extracellular fluid Paracrine signaling Electrical signal along nerve cell triggers release of neurotransmitter Endocrine cell Neurotransmitter diffuses across synapse Secretory vesicle Target cell is stimulated Blood vessel Hormone travels in bloodstream to target cells Target cell Synaptic signaling Hormonal signaling (a) Paracrine signaling- A secreting cell acts on nearby target cells by discharging molecules of a local regulator (a growth factor, for example) into the extracellular fluid. (b) Synaptic signaling- A nerve cell releases neurotransmitter molecules into a synapse, stimulating the target cell (c) Hormonal signalingspecialized endocrine cells secrete hormones into body fluids, often the blood. Hormones may reach virtually all body cells 3 Stages of Cell Signaling: 1. Reception: Detection of a signal molecule (ligand) coming from outside the cell 2. Transduction: Convert signal to a form that can bring about a cellular response 3. Response: Cellular response to the signal molecule EXTRACELLULAR FLUID CYTOPLASM Plasma membrane Reception Transduction Receptor Signal molecule 1. Reception- Reception is the target cells detection of a signal molecule coming from outside the cell. A chemical signal is “detected” when it binds to a receptor protein located at the cell’s surface or inside the cell EXTRACELLULAR FLUID CYTOPLASM Plasma membrane Reception Transduction Receptor Relay molecules in a signal transduction pathway Signal molecule 2. Transduction- The binding of the signal molecule changes the receptor protein in some way, initiating the process of transduction. The transduction stage converts the signal to a form that can bring about the specific cellular response. Transduction sometimes occurs in a single step but more often requires a sequence of changes in a series of different molecules- a signal transduction pathway. The molecules in the pathway are often called relay molecules. EXTRACELLULAR FLUID CYTOPLASM Plasma membrane Reception Transduction Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Signal molecule 3. Response- In the third stage of cell signaling, the transduced signal finally triggers a specific cellular response. The response may be almost any imaginable cellular activity- such as catalysis by an enzyme, rearrangement of the cytoskeleton, or activation of specific genes in the nucleus. The cell signaling process helps ensure that crucial activities like these occur in the right cells, at the right time, and in proper coordination with the other cells of the organism. 1. Reception Binding between signal molecule (ligand) + receptor is highly specific. Types of Receptors: a) Plasma membrane receptor water-soluble ligands b) Intracellular receptors (cytoplasm, nucleus) hydrophobic or small ligands Eg. testosterone or nitric oxide (NO) Ligand binds to receptor protein protein changes SHAPE initiates transduction signal Receptors in the Plasma Membrane Most water-soluble signal molecules bind to specific sites on receptor proteins in the plasma membrane There are three main types of membrane receptors: G-protein-linked receptors Receptor tyrosine kinases Ion channel receptors G-Protein-Coupled Receptor A G-protein-linked receptor is a plasma membrane receptor that works with the help of a G protein The G-protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive These are extremely widespread and diverse in their functions, including roles in embryonic development and sensory reception They are also involved in many human diseases, including bacterial infections. Up to 60% of all medicines used today exert their effects by influencing G-protein pathways G-Protein-Coupled Receptor Receptor Tyrosine Kinase Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines A receptor tyrosine kinase can trigger multiple signal transduction pathways at once Receptor Tyrosine Kinase 1. Many receptor tyrosine kinases have the structure depicted schematically here. Before the signal molecule binds, the receptors exist as individual polypepitides. Notice that each has an extracellular signal-binding site, and alpha helix spanning the membrane, an intracellular tail containing multiple tyrosines. 3. Dimerization activates the tyrosinekinase region of each polypeptide; each tyrosine kinase adds a phosphate from an ATP molecule to a tyrsine on the tail of the other polypeptide. 2. The binding of a signal molecule (such as a growth factor) causes two receptor polypeptides to associate closely with each other, forming a dimer (dimerization) 4. Now that the receptor protein is fully activated, it is recognized by specific relay proteins inside the cell. Each such protein binds to a specific phosphorylated tyrosine, undergoing a resulting structural change that activates the bound protein. Each activated protein triggers a transduction pathway, leading to a cellular response. EXPLANATION OF STEPS ON PREVIOUS SLIDE Ligand-Gated Ion Channel An ion channel receptor acts as a gate when the receptor changes shape When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na+ or Ca2+, through a channel in the receptor 1. Here we show a ligand-gated ion channel receptor in which the gate remains closed until a ligand binds to the receptor Signal molecule (ligand) Gate closed Ligand-gated ion channel receptor 2. When the ligand binds to the receptor and the gate opens, specific ions can flow through the channel and rapidly change the concentration of that particular ion inside the cell. This change may directly affect the activity of the cell in some way. Ions Plasma membrane Gate open Cellular response Gate closed 3. When the ligand dissociates from this receptor, the gate closes and ions no longer enter the cell. Plasma Membrane Receptors Overview G-Protein Coupled Receptor (GPCR) Tyrosine Kinase Ligand-Gated Ion Channels 7 transmembrane segments in membrane Attaches (P) to tyrosine Signal on receptor changes shape G protein + GTP activates enzyme cell response Activate multiple cellular responses at once Regulate flow of specific ions (Ca2+, Na+) Intracellular Receptors Some receptor proteins are intracellular, found in the cytosol or nucleus of target cells Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors Examples of hydrophobic messengers are the steroid and thyroid hormones of animals An activated hormone-receptor complex can act as a transcription factor, turning on specific genes LE 11-6 Hormone (testosterone) Steroid hormone interacting with an intracellular receptor EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormonereceptor complex The steroid hormone testosterone passes through the plasma membrane. Testosterone binds to a receptor protein in the cytoplasm, activating it. The hormonereceptor complex enters the nucleus and binds to specific genes. DNA The bound protein stimulates the transcription of the gene into mRNA. mRNA NUCLEUS New protein The mRNA is translated into a specific protein. CYTOPLASM 2. Transduction Cascades of molecular interactions relay signals from receptors target molecules Protein kinase: enzyme that phosphorylates and activates proteins at next level Phosphorylation cascade: enhance and amplify signal These multistep pathways provide more opportunities for coordination and regulation Signal Transduction Pathways The molecules that relay a signal from receptor to response are mostly proteins Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated At each step, the signal is transduced into a different form, usually a conformational change In many pathways, the signal is transmitted by a cascade of protein phosphorylations Phosphatase enzymes remove the phosphates This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off LE 11-8 Signal molecule 1. A relay molecule activates protein kinase 1 Receptor Activated relay molecule Inactive protein kinase 1 2. Active protein kinase 1 transfers a phosphate from ATP to an inactive molecule of protein kinase 2, thus activating this second kinase 3. Active Protein kinase 2 then catalyzes the P Active phosphorylation (and protein activation) of protein kinase kinase 3 2 Active protein kinase 1 Inactive protein kinase 2 5. Enzymes called protein phosphatases (PP) catalyze the removal of phosphate groups from the proteins, making them inactive and available for reuse. ATP ADP Pi PP Inactive protein kinase 3 ATP ADP Pi Active protein kinase 3 PP Inactive protein ATP ADP Pi PP P 4. Finally, active protein kinase 3 phosphorylates a protein (pink) that brings about the cell’s response to the signalP Active protein Cellular response Small Molecules and Ions as Second Messengers Second messengers are small, nonprotein, watersoluble molecules or ions The extracellular signal molecule that binds to the membrane is a pathway’s “first messenger” Second messengers can readily spread throughout cells by diffusion Second messengers participate in pathways initiated by G-protein-linked receptors and receptor tyrosine kinases Second Messengers small, nonprotein molecules/ions that can relay signal inside cell Second messengers participate in pathways initiated by G-protein-linked receptors and receptor tyrosine kinases Eg. cyclic AMP (cAMP), calcium ions (Ca2+), inositol triphosphate (IP3) Cyclic AMP • Cyclic AMP (cAMP) is one of the most widely used second messengers The second messenger cyclic AMP (cAMP) is made from ATP by adenylyl cyclase, an enzyme embedded in the plasma membrane. Cyclic AMP is inactivated by phosphodiesterase, an enzyme that converts it to AMP cAMP cAMP = cyclic adenosine monophosphate GPCR adenylyl cyclase (convert ATP cAMP) activate protein kinase A cAMP as a second messenger in a G-protein-signaling pathway. The first messenger activates a Gprotein-linked receptor, which activates a specific G protein. In turn, the G protein activates adenylyl cyclase, which catalyzes the conversion of ATP to cAMP. The cAMP then activates another protein, usually protein kinase A Second Messengers- Calcium ions Calcium ions (Ca2+) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration LE 11-11 The maintenance of calcium ion concentrations in an animal cell. The calcium concentration in the cytosol is usually lower than in the extracellular fluid and ER. Protein pumps in the plasma membrane and the ER membrane, driven by ATP, move calcium from the cytosol into the extracellular fluid and into the lumen of the ER. Mitochondrial pumps, driven by chemiosmosis, move calcium into the mitochondria when the calcium level in the cytosol rises EXTRACELLULAR FLUID Plasma membrane Ca2+ pump ATP Mitochondrion Nucleus CYTOSOL Ca2+ pump Endoplasmic reticulum (ER) ATP Key Ca2+ pump High [Ca2+] Low [Ca2+] Second Messengers- Inositol Triphosphate (IP3) A signal relayed by a signal transduction pathway may trigger an increase in calcium in the cytosol Pathways leading to the release of calcium involve inositol triphosphate (IP3) and diacylglycerol (DAG) as second messengers LE 11-12_1 EXTRACELLULAR Signal molecule FLUID (first messenger) 1. A signal molecule binds to a receptor, leading to activation of phospholipase C 2. Phospholipase C cleaves a plasma membrane phospholipid called PIP2 into DAG and IP3 DAG functions as a second messenger in other pathways G protein DAG GTP G-protein-linked receptor Phospholipase C PIP2 IP3 (second messenger) IP3-gated calcium channel Endoplasmic Ca2+ reticulum (ER) CYTOSOL 4. IP3 quickly diffuses through the cytosol and binds to an IP3 gated calcium channel in the ER membrane, causing it to open LE 11-12_2 EXTRACELLULAR Signal molecule FLUID (first messenger) G protein DAG GTP G-protein-linked receptor Phospholipase C PIP2 IP3 (second messenger) IP3-gated calcium channel Endoplasmic Ca2+ reticulum (ER) CYTOSOL Ca2+ (second messenger) 5. Calcium ions flow out of the ER (down the concentration gradient), raising the calcium level in the cytosol LE 11-12_3 EXTRACELLULAR Signal molecule FLUID (first messenger) G protein DAG GTP G-protein-linked receptor Phospholipase C PIP2 IP3 (second messenger) IP3-gated calcium channel Endoplasmic Ca2+ reticulum (ER) CYTOSOL Ca2+ (second messenger) Various proteins activated Cellular responses 6. The calcium ions activate the next protein in one or more signaling pathways 3. Response Regulate protein synthesis by turning on/off genes in nucleus (gene expression) Regulate activity of proteins in cytoplasm Fine-Tuning of the Response Multistep pathways have two important benefits: Amplifying the signal (and thus the response) Contributing to the specificity of the response The Specificity of Cell Signaling Different kinds of cells have different collections of proteins These differences in proteins give each kind of cell specificity in detecting and responding to signals The response of a cell to a signal depends on the cell’s particular collection of proteins Pathway branching and “cross-talk” further help the cell coordinate incoming signals LE 11-15 Signal molecule Receptor Relay molecules Response 1 Cell A. Pathway leads to a single response Response 2 Response 3 Cell B. Pathway branches, leading to two responses Activation or inhibition Response 4 Cell C. Cross-talk occurs between two pathways Response 5 Cell D. Different receptor leads to a different response Signal Transduction Pathway Problems/Defects: Examples: Diabetes Cholera Autoimmune disease Cancer Neurotoxins, poisons, pesticides Drugs (anesthetics, antihistamines, blood pressure meds) Cholera Toxin modifies G-protein Disease acquired by drinking contaminated water (w/human feces) Bacteria (Vibrio cholerae) colonizes lining of small intestine and produces toxin involved in regulating salt & water secretion G protein stuck in active form intestinal cells secrete salts, water Infected person develops profuse diarrhea and could die from loss of water and salts Viagra Used as treatment for erectile dysfunction Inhibits hydrolysis of cGMP GMP Prolongs signal to relax smooth muscle in artery walls; increase blood flow to penis Viagra inhibits cGMP breakdown Apoptosis = cell suicide Cell is dismantled and digested Triggered by signals that activate cascade of “suicide” proteins (caspase) Why? Protect neighboring cells from damage Animal development & maintenance May be involved in some diseases (Parkinson’s, Alzheimer’s) Apoptosis of a human white blood cell Left: Normal WBC Right: WBC undergoing apoptosis – shrinking and forming lobes (“blebs”) Effect of apoptosis during paw development in the mouse