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Intercellular Communication: Receptors Intercellular Communication: Receptors Sue Keirstead, Ph.D. Dept. of Integrative Biology and Physiology [email protected] 612 626 2290 Class 3: Intercellular Communication – Learning Objectives 1. Compare and contrast the 3 main methods by which cells communicate with one another: 1) gap junctions, 2) cell-to cell-binding, 3) extracellular chemical messengers. Provide an example of cell types that use each of these methods. 2. Compare and contrast intracellular receptors and plasma membrane receptors; consider the chemical nature of the ligands (i.e. chemical messengers), location of the receptors in/on the cell, and consequences of ligand-receptor binding. Provide an example of each type of receptor. 3. Describe the three main types of extracellular chemical messengers: 1) hormones, 2) local mediators, and 3) neurotransmitters. Provide an example of each type of chemical messenger and which cells use it to communicate with other cells. 4. Compare and contrast the following 4 types of plasma membrane receptors: 1) ion channel receptors, 2) receptor enzymes, 3) enzyme-couple receptors, 4) G protein-coupled receptors. Consider ligand- binding/specificity, coupling with other proteins, consequences of ligand binding, and signal transduction pathways. 5. Map the steps that occur as a result of activation of a G protein-coupled receptor. Using the cAMP transduction pathway as an example of a second messenger system, draw a flow chart that illustrates how signal amplification occurs. 6. Describe two ways in which activation of G protein-coupled receptors can lead to a change in ion channel function (Figure 6.25). Compare and contrast the latency (time to onset of the change in membrane potential), duration, and amplitude of the responses produced by each of these. How do these compare to the changes in membrane potential that are triggered by activation of ion channel receptors? Draw the changes in membrane potential that you would expect to see as a result of binding of ligands in each of these three scenarios. 7. Define the terms affinity, specificity, agonist and antagonist as related to receptor ligands. 8. Contrast the cell-to-cell communication at a chemical synapse with that at a gap junction (electrical synapse) based on speed, fidelity (i.e. how does the size and shape of the signal compare in the cell initiating the signal versus the cell receiving the signal?), and the ability to reverse the direction of the electrical signal (i.e. excitation or inhibition). Gap junction Ions and small molecules Cell 1 Cell 2 Connexon Surface molecules Cell 1 Cell 2 Figure 6.1 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Extracellular Chemical Messengers Local mediators Hormones (transported in blood) Neurotransmitters Figure 6.3 Lipid-soluble messenger (e.g. steroid hormone) 1 Nucleus Intracellular Receptor 2 DNA 3 mRNA 4 Ribosome New protein (effector protein) 5 Cellular response Target cell Figure 6.15 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Receptor Specificity Secreting cell Extracellular chemical messenger Receptor Receptor Nontarget cell Nontarget cell Receptor Target cell Figure 6.7 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Saturation Percent of receptorsPercent bound messenger by Concentration of messenger Figure 6.8 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Competition Norepinephrine Norepinephrine Epinephrine Epinephrine β1 receptor β2 receptor Similar affinity Higher affinity for for epinephrine norepinephrine & epinephrine Which agonist will bind to the receptor is determined by: 1. The affinity of the receptor binding site for the each agonist 2. The concentration of each agonist Figure 6.9 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Types of Plasma Membrane Receptors 1. Ion channel receptors (= ligand-gated channels) 2. G protein-coupled receptors 3. Receptor enzymes 4. Enzyme–coupled receptors Extracellular fluid Ion channel receptor: Messenger-binding site Ion channel Plasma membrane Cytosol Figure 6.17 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Ion channel receptor (ligand-gated channel) Water-soluble extracellular Extracellular fluid messenger (ligand) Ion channel receptor Ions 1 3 2 Plasma 4 membrane Cellular response Cytosol Ions move through channels down their electrochemical gradient Movement of ions through channels leads to a change in membrane potential Figure 6.17 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Components of a Receptor Enzyme Extracellular fluid e.g. Receptor tyrosine kinase: Messenger-binding site Transmembrane segment Plasma membrane Tyrosine kinase Cytosol Figure 6.18 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Signaling pathway involving a receptor tyrosine kinase Water-soluble extracellular Extracellular fluid messenger Receptor tyrosine 1 kinase 2 3 4 Plasma P P P P P P membrane 5 Inactive relay P protein (docked) Active relay protein (docked) 6 7 Inactive relay Intracellular Effector Cellular Cytosol protein pathways protein response Tyrosine kinase – enzyme that phosphorylates (adds a phosphate group to) a protein Phosphorylating a protein modifies its function (e.g. activates it) Figure 6.18 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Components of an enzyme-coupled receptor Extracellular fluid Enzyme-coupled receptor: Messenger-binding site Transmembrane segment Plasma Enzyme Site coupled to enzyme membrane (example: janus kinase) Cytosol Figure 6.20 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Signaling pathway involving an enzyme-coupled receptor Water-soluble extracellular Extracellular fluid messenger Enzyme-coupled receptor 2 1 3 P P P P P P Plasma P P P P P P membrane Janus kinase Active STAT Inactive STAT (docked) 4 P (docked) 5 Inactive STAT Active STAT is released and then 6 enters nucleus P Effector protein Nucleus 7 8 Increased transcription of Increased synthesis causes cellular of effector protein Cytosol gene for effector protein response Figure 6.20 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Extracellular fluid G protein-coupled receptor: Messenger-binding site Transmembrane segment Site coupled to G protein Plasma membrane G protein Cytosol Figure 6.21 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. G protein function Water-soluble extracellular messenger 2 G protein-coupled receptor Target protein 1 3 α γ β GTP Activated G protein α γ γ α β β GDP GTP Inactive G protein Activity of target protein is altered by a subunit of G protein 5 4 α γ γ α β β GDP GDP P Figure 6.22 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Water-soluble extracellular Extracellular fluid messenger 1 G protein-coupled receptor Plasma Adenylyl cyclase membrane 3 4 2 Gs protein ATP cAMP 5 Effector protein 6 Protein Protein kinase A kinase A (inactive) (active) P 7 Effector protein Cellular (phosphorylated) Cytosol response Figure 6.23 Copyright © 2019 by John Wiley & Sons, Inc. All rights reserved. Amplification through G protein-coupled receptor signaling pathways 1. A single receptor can be coupled to many G proteins 2. In turn, many target proteins (e.g. adenylyl cyclase) can be activated by the many G protein α subunits that are activated 3. If the target proteins are enzymes (like adenylyl cyclase), then each of these can catalyse the reaction (i.e. generate cAMP) many times until they are inactivated as long as substrate (e.g. ATP) is available or the enzymes are activated 4. All of the resultant cAMP molecules generated can each activate a PKA (protein kinase A) enzyme 5. Each of the activated PKA proteins can catalyse the phosphorylation of many proteins Draw a diagram to illustrate the various stages of amplification in this pathway. Class 3: Intercellular Communication – Learning Objectives 1. Compare and contrast the 3 main methods by which cells communicate with one another: 1) gap junctions, 2) cell-to cell-binding, 3) extracellular chemical messengers. Provide an example of cell types that use each of these methods. 2. Compare and contrast intracellular receptors and plasma membrane receptors; consider the chemical nature of the ligands (i.e. chemical messengers), location of the receptors in/on the cell, and consequences of ligand-receptor binding. Provide an example of each type of receptor. 3. Describe the three main types of extracellular chemical messengers: 1) hormones, 2) local mediators, and 3) neurotransmitters. Provide an example of each type of chemical messenger and which cells use it to communicate with other cells. 4. Compare and contrast the following 4 types of plasma membrane receptors: 1) ion channel receptors, 2) receptor enzymes, 3) enzyme-couple receptors, 4) G protein-coupled receptors. Consider ligand- binding/specificity, coupling with other proteins, consequences of ligand binding, and signal transduction pathways. 5. Map the steps that occur as a result of activation of a G protein-coupled receptor. Using the cAMP transduction pathway as an example of a second messenger system, draw a flow chart that illustrates how signal amplification occurs. 6. Describe two ways in which activation of G protein-coupled receptors can lead to a change in ion channel function (Figure 6.25). Compare and contrast the latency (time to onset of the change in membrane potential), duration, and amplitude of the responses produced by each of these. How do these compare to the changes in membrane potential that are triggered by activation of ion channel receptors? Draw the changes in membrane potential that you would expect to see as a result of binding of ligands in each of these three scenarios. 7. Define the terms affinity, specificity, agonist and antagonist as related to receptor ligands. 8. Contrast the cell-to-cell communication at a chemical synapse with that at a gap junction (electrical synapse) based on speed, fidelity (i.e. how does the size and shape of the signal compare in the cell initiating the signal versus the cell receiving the signal?), and the ability to reverse the direction of the electrical signal (i.e.
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