Cell Communication Signal Transduction External signal is received
- Slides: 48
Cell Communication – Signal Transduction External signal is received and converted to another form to elicit a response 1
Signal Transduction & G Protein-coupled Receptors Topics • Signal Trans. : From Extracellular Signal to Cellular Response • Cell-Surface Receptors & Signal Transduction Proteins • G Protein-coupled Receptors (GPCRs): Structure and Mechanism • GPCRs That Regulate Ion Channels • GPCRs That Regulate Adenylyl Cyclase • GPCRs That Regulate Cytosolic Calcium
Learning Objectives • Learn the general properties of signaling molecules (ligands), cellsurface receptors, & intracellular signal transduction components. • Learn the G protein cycle of reactions involved in GPCR signaling. • Learn the epinephrine receptor signal trans pathway used for control of glycogen degradation. • Learn about the GPCR-stimulated IP 3/DAG signaling pathway.
General Principles of Signal Transduction Signal transduction refers to the overall process of converting extracellular signals into intracellular responses. Key players in signal transduction are signaling molecules, receptors, signal transduction proteins and second messengers, and effector proteins.
Cells respond to signals by changing the activity of existing enzymes (fast) and/or the levels of expression of enzymes and cell components (slower) by gene regulation (Steps 7 a & 7 b). Receptors and signal transduction systems have evolved to detect and respond to hormones, growth factors, drugs , neurotransmitters.
Intercellular Communication
Intercellular Communication between cells requires: ligand: the signaling molecule receptor protein: the molecule to which the receptor binds -may be on the plasma membrane or within the cell 7
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Structure and function of receptors • Globular proteins acting as a cell’s ‘letter boxes’ • Located mostly in the cell membrane • Receive messages from chemical messengers coming from other cells • Transmit a message into the cell leading to a cellular effect • Different receptors specific for different chemical messengers • Each cell has a range of receptors in the cell membrane making it responsive to different chemical messengers
Mechanism • Receptors contain a binding site (hollow or cleft in the receptor surface) that is recognised by the chemical messenger • Binding of the messenger involves intermolecular bonds • Binding results in an induced fit of the receptor protein • Change in receptor shape results in a ‘domino’ effect • Domino effect is known as Signal Transduction, leading to a chemical signal being received inside the cell • Chemical messenger does not enter the cell. It departs the receptor unchanged and is not permanently bound
Overall process of receptor/messenger interaction M M M RE RE R Signal transduction • • • Binding interactions must be: - strong enough to hold the messenger sufficiently long for signal transduction to take place - weak enough to allow the messenger to depart Implies a fine balance Drug design - designing molecules with stronger binding interactions results in drugs that block the binding site antagonists
Messenger binding Bonding forces • • • Ionic H-bonding van der Waals Example: vdw interaction H-bond Binding site O Ser H ionic bond CO 2 Asp Receptor Phe
How does the Binding Site Change Shape? Substrate binding • Bonding forces • Induced fit - Binding site alters shape to maximise intermolecular bonding Phe O O H Ser CO 2 Asp Intermolecular bonds not optimum length for maximum binding strength Induced Fit Ser H CO 2 Asp Intermolecular bond lengths optimised
External signals are converted to Internal Responses • Cells sense and respond to the environment Prokaryotes: chemicals Humans: light - rods & cones of the eye sound – hair cells of inner ear chemicals in food – nose & tongue • Cells communicate with each other Direct contact Chemical signals 14
General principles: 1. Signals act over different ranges. 2. Signals have different chemical natures. 3. The same signal can induce a different response in different cells. 4. Cells respond to sets of signals. 5. Receptors relay signals via intracellular signaling cascades. 15
1º messenger Effector Enzymes Target Enzymes Cells detect signal & respond 2º messengers Signal transduction: ability of cell to translate receptor-ligand interaction into a change in behavior or gene expression 16
Primary Messenger EXTRACELLULAR FLUID 1 Reception Target Enzymes Secondary Messengers CYTOPLASM Plasma membrane 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Signal molecule Cascade Effect 17
Each protein in a signaling pathway – Amplifies the signal by activating multiple copies of the next component in the pathway primary signal - activates an enzyme activity, processes 100 substrates /second Primary enzyme activates 100 target enzymes Each of the 100 enzymes activates an additional 100 downstream target enzymes Each of the 10, 000 downstream targets activates 100 control factors so rapidly have 1, 000 active control factors 18
A Signal Cascade Reception Binding of epinephrine to G-protein-linked receptor (1 molecule) 1 Transduction amplification Inactive G protein Active G protein (102 molecules) Inactive adenylyl cyclase 102 Active adenylyl cyclase (102) ATP Cyclic AMP (104) Inactive protein kinase A Active protein kinase A (104) Inactive phosphorylase kinase Active phosphorylase kinase (105) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) Response Glycogen Glucose-1 -phosphate (108 molecules) 104 105 106 8 19 10
Receptors relay signals via intracellular SIGNALING CASCADES 20
Main Types of Receptors • ION CHANNEL RECEPTORS • G-PROTEIN-COUPLED RECEPTORS • KINASE-LINKED RECEPTORS • INTRACELLULAR RECEPTORS
Cell-surface receptors -large &/or hydrophilic ligands ion-channel-linked Trimeric G-protein-linked enzyme-linked (tyrosine kinase) 22
Signal transduction Control of ion channels • Receptor protein is part of an ion channel protein complex • Receptor binds a messenger leading to an induced fit • Ion channel is opened or closed • Ion channels are specific for specific ions (Na+, Ca 2+, Cl-, K+) • Ions flow across cell membrane down concentration gradient • Polarises or depolarises nerve membranes • Activates or deactivates enzyme catalysed reactions within cell
Ion channel receptors Examples: Muscle Contraction Signal molecule (ligand) Gate closed Ligand-gated ion channel receptor Ions Plasma Membrane Gate open Nerve Cell communication Cellular response Gate close 24
Review: Remember the Na+/K+ ATPase (Na+/K+ pump)? [Na+] inside ~10 m. M; outside ~150 m. M [K+] inside ~100 m. M; outside ~5 m. M cell has membrane potential ~ -60 m. V Na+ Cl-60 m. V K+ A- + + - -- + + 25
Intercellular Communication There are four basic mechanisms for cellular communication: 1. direct contact 2. paracrine signaling 3. endocrine signaling 4. synaptic signaling 26
Intercellular Communication Direct contact – molecules on the surface of one cell are recognized by receptors on the adjacent cell 27
Intercellular Communication Paracrine signaling – signal released from a cell has an effect on neighboring cells local ex. nitric oxide, histamines, prostaglandins 28
Intercellular Communication Endocrine signaling – hormones released from a cell affect other cells throughout the body long distance ex. Estrogen, Thyroxine, GH Epinephrine …. 29
Intercellular Communication Synaptic signaling – nerve cells release the signal (neurotransmitter) which binds to receptors on nearby cells 30
Intercellular Communication When a ligand binds to a receptor protein, the cell has a response. signal transduction: the events within the cell that occur in response to a signal Different cell types can respond differently to the same signal. 31
Receptor Types There are 3 subclasses of membrane receptors: 1. channel linked receptors – ion channel that opens in response to a ligand 2. enzymatic receptors – receptor is an enzyme that is activated by the ligand 3. G protein-coupled receptor – a G-protein (bound to GTP) assists in transmitting the signal 32
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Intercellular Communication A cell’s response to a signal often involves activating or inactivating proteins. Phosphorylation is a common way to change the activity of a protein kinase – an enzyme that adds a phosphate to a protein phosphatase – an enzyme that removes a phosphate from a protein 34
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Signal Transduction Components: Kinases/Phosphatases Proteins that participate in intracellular signal transduction fall into two main classes--protein kinases/phosphatases and GTPase switch proteins. Kinases use ATP to phosphorylate amino acid side-chains in target proteins. Kinases typically are specific for tyrosine or serine/threonine sites. Phosphatases hydrolyze phosphates off of these residues. Kinases and phosphatases act together to switch the function of a target protein on or off.
Kinases - Phosphorylation Phosphatase - Dephosphorylation Tyrosine-OH Tyr-Kinases Serine-OH Threonine-OH Ser/Thr-Kinases „dual specificity“ Kinases
There about 600 kinases and 100 phosphatases encoded in the human genome. Activation of many cell-surface receptors leads directly or indirectly to changes in kinase or phosphatase activity. Note that some receptors are themselves kinases (e. g. , the insulin receptor).
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Growth hormone receptor Tetrameric complex constructed in presence of growth hormone GH GH binding & dimerisation Binding of kinases GH receptors (no kinase activity) Activation and phosphorylation ATP HO kinases OH HO OH OH Growth hormone binding site Kinase active site OH OH OH Kinase active site opened by induced fit ADP PO OP OP OP
Intracellular receptors • Chemical messengers must cross cell membrane CO 2 H • Chemical messengers must be hydrophobic • Example-steroids and steroid receptors Steroid binding region Zinc DNA binding region (‘zinc fingers’) H 2 N Zinc fingers contain Cys residues (SH) Allow S-Zn interactions
Intracellular Receptors steroid hormones -have a nonpolar, lipid-soluble structure -can cross the plasma membrane to a steroid receptor -usually affect regulation of gene expression An inhibitor blocks the receptor from binding to DNA until the hormone is present. 43
Intracellular receptor Mechanism Co-activator protein Receptor DNA Messenger Receptor-ligand complex Dimerisation Cell membrane 1. Messenger crosses membrane 2. Binds to receptor 3. Receptor dimerisation 4. Binds co-activator protein 5. Complex binds to DNA 6. Transcription switched on or off 7. Protein synthesis activated or inhibited
Intracellular Receptors A steroid receptor has 3 functional domains: 1. hormone-binding domain 2. DNA binding domain 3. domain that interacts with coactivators to affect gene expression 45
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END PART I
Important Announcement • Final Exam will include 4 lectures from mid-term exam material only from L 5, 6, 7 & 8. • The First 4 lectures are NOT required. • The distribution of marks in the final exam will be as follow : The lectures after the mid exam = 40 % The mid-term lectures will have =10 % GOOD LUCK
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