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    1. 1. Membranes and receptors Lecture 8 PJ Booth <ul><li>Introduction to biological membranes </li></ul><ul><ul><li>Lipids & cholesterol </li></ul></ul><ul><ul><li>Membrane proteins </li></ul></ul><ul><li>G protein coupled receptors </li></ul><ul><li>Transporters </li></ul><ul><ul><li>Glucose transport </li></ul></ul>Medical Biochemistry, Baynes & Dominiczak chap7Dow, Lindsay Morrison chap 3
    2. 2. Biological membrane
    3. 3. What is membrane fluidity? Individual lipid molecules move Chains, headgroups move Lipids themselves diffuse laterally
    4. 4. Phospholipid structures Phosphatidylethanolamine PE
    5. 5. Cholesterol why is it a major constituent of eukaryotic plasma membranes? polar Rigid steroid ring structure Hydrocarbon tail
    6. 6. Cholesterol why is it a major constituent of eukaryotic plasma membranes? polar Rigid steroid ring structure Hydrocarbon tail Prevents chain “freezing” Ends of chains still relatively free to move Restricts movement of lipid chain
    7. 7. What do membranes do? <ul><li>Control flow of nutrients, ions, drugs, waste products </li></ul><ul><ul><li>transport </li></ul></ul><ul><ul><li>maintain concentration gradients </li></ul></ul><ul><li>Communication </li></ul><ul><ul><li>receptors & signalling between cells </li></ul></ul><ul><li>Electron transfer, proton pumping & ATP synthesis </li></ul><ul><ul><li>mitochondria </li></ul></ul><ul><ul><li>Chloroplasts </li></ul></ul>
    8. 8. G protein coupled receptors
    9. 9. What do G protein receptors do? - binds to the receptor - receptor changes shape & binds the G protein Extracellular signal molecule = stimulus The G protein  subunit binds GTP & the G protein splits into 2 activated components
    10. 10. G protein coupled receptors Receptor Stimulus Effector Response  adrenergic Adrenalin Adenylate cyclase Heart rate acceleration Serotonin Serotonin Adenylate cyclase Many eg neuronal excitability Glucagon Glucagon Adenylate cyclase Glycogen breakdown Rhodopsin Light cGMP phophodiesterase Visual excitation Muscarinic types Acetylcholine Adenylate cyclase Phospholipase C K + channel Excitation/inhibition of neurons Slowing of heart rate Generate cyclic AMP
    11. 11. Membrane transport Lecture 10 PJ Booth <ul><li>Types of transport and transporters </li></ul><ul><li>Glucose transport </li></ul><ul><li>ABC transporters </li></ul>Medical Biochemistry, Baynes & Dominiczak chap 7, also sections in Stryer and “Molecular Biology of the Cell”, Alberts et al., Garland publishing
    12. 12. Membrane transport
    13. 13. How do molecules or ions cross membranes? via membrane proteins
    14. 14. How do molecules cross membranes? via membrane proteins <ul><ul><li>down a concentration gradient </li></ul></ul><ul><li>Uniporters </li></ul><ul><li>Symporters </li></ul><ul><ul><li>transport in same direction </li></ul></ul><ul><li>Antiporters </li></ul><ul><ul><li>transport in opposite directions </li></ul></ul>
    15. 15. How do molecules cross membranes? via membrane proteins <ul><ul><li>down a concentration gradient </li></ul></ul><ul><ul><ul><li>primary -ATP </li></ul></ul></ul><ul><ul><ul><li>secondary -ions eg Na+ </li></ul></ul></ul><ul><ul><ul><li>accumulate against a concentration gradient </li></ul></ul></ul>
    16. 16. Primary & secondary active transport primary secondary
    17. 17. Na + /K + ATPase or pump
    18. 18. Na + /K + ATPase an example of primary transport <ul><li>Plasma membrane of virtually all animal cells </li></ul><ul><li>Pumps Na + ions out & K + ions into the cell </li></ul><ul><ul><li>maintains concentration difference of about 10-30 fold across the bilayer, by hydrolysing ATP </li></ul></ul><ul><li>Maintains a Na + gradient that is used to drive uptake of nutrients, e.g. glucose </li></ul><ul><ul><li>use primary ATP-driven transport to create the Na+ gradient to drive secondary transport </li></ul></ul>
    19. 19. Glucose transporters <ul><li>Active transport is necessary in the gut and kidneys </li></ul><ul><li>Na + -linked glucose transport </li></ul><ul><ul><li>Secondary transport of glucose, using Na + ion gradient as the energy source </li></ul></ul><ul><ul><li>Na + gradient is maintained by Na/K ATPase </li></ul></ul>
    20. 20. Glucose transporters <ul><li>5 closely related passive glucose transporters </li></ul><ul><ul><li>GLUT1 red blood cells </li></ul></ul><ul><ul><li>GLUT2 liver, kidney, pancreas </li></ul></ul><ul><ul><li>GLUT3 neurons, brain </li></ul></ul><ul><ul><li>GLUT4 muscle, adipose tissue insulin sensitive </li></ul></ul><ul><ul><li>GLUT5 intestine, brain </li></ul></ul><ul><li>approx. 500 amino acids </li></ul><ul><li>12 transmembrane  helices </li></ul><ul><li>Active Na + -linked glucose transporter </li></ul>
    21. 21. Na + - linked & passive glucose transport GLUT2
    22. 22. Glucose transporters <ul><li>5 closely related passive glucose transporters </li></ul><ul><ul><li>GLUT1 red blood cells </li></ul></ul><ul><ul><li>GLUT2 liver, kidney, pancreas </li></ul></ul><ul><ul><li>GLUT3 neurons, brain </li></ul></ul><ul><ul><li>GLUT4 muscle, adipose tissue insulin sensitive </li></ul></ul><ul><ul><li>GLUT5 intestine, brain </li></ul></ul><ul><li>approx. 500 amino acids </li></ul><ul><li>12 transmembrane  helices </li></ul><ul><li>GLUT4 and insulin </li></ul><ul><ul><li>only found in muscle and adipose tissue when insulin is present </li></ul></ul><ul><li>Active Na + -linked glucose transporter </li></ul>
    23. 23. GLUT4 and insulin
    24. 24. Cystic fibrosis – ABC transporters <ul><li>Thick mucous secretions that block small airways of lungs and pancreatic ducts </li></ul><ul><ul><li>fatal-progressive destruction of lungs and pancreas </li></ul></ul><ul><li>Failure in chloride transport </li></ul><ul><ul><li>mutations in the gene for the CFTR chloride channel (cystic fibrosis transmembrane conductance regulator) </li></ul></ul><ul><ul><li>CFTR chloride channel reside in epithelial cells in lungs and secrectory ducts of pancreas </li></ul></ul><ul><ul><ul><li>Chloride transport is accompanied by water transport </li></ul></ul></ul><ul><ul><ul><li>failure in chloride transport reduces the fluid produced by the epithelial cells of lung airways and pancreatic ducts that become blocked by thick secretions </li></ul></ul></ul>
    25. 25. Cystic fibrosis transmembrane conductance regulator CFTR <ul><li>part of the ABC transporter family </li></ul><ul><ul><li>A TP b inding c assette transporters </li></ul></ul><ul><ul><li>Primary transport </li></ul></ul>ATP binding sites
    26. 26. Multidrug resistance <ul><li>Multidrug resistant protein, MDR </li></ul><ul><ul><li>ABC transporter </li></ul></ul><ul><li>overexpressed in cancer cells which then become resistant to a wide range of drugs </li></ul><ul><ul><li>Up to 40% of human cancers develop multidrug resistance </li></ul></ul><ul><li>Malaria </li></ul><ul><ul><li>Resistance of Plasmodiun falciparum to antimalarial drug, chloroquinone </li></ul></ul><ul><ul><li>Pumped out by an ABC transporter </li></ul></ul>
    27. 27. Summary passive Uniport Glucose GLUT 2 active Secondary symport Glucose & Na + Na + -linked glucose transporter active Primary Cl - ABC transporter CFTR active Primary antiport Na + & K + ATPase Na + /K + ATPase Type of transport Species transported Type of protein Membrane protein transporter
    28. 28. Summary of what you need to know <ul><li>Membrane properties & function </li></ul><ul><ul><li>Lipids </li></ul></ul><ul><ul><li>Cholesterol </li></ul></ul><ul><ul><li>Protein structures </li></ul></ul><ul><li>General structure and function of G protein coupled receptors with example </li></ul><ul><ul><li>Note conformational changes of the membrane protein are required </li></ul></ul>

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