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Lecture 11: GPCR pathways

Lecture 11: GPCR pathways. Fain Chapter 4 10/7/09. Kao - high transmission fiber optic cables from pure materials. Fiber optic networks. Current amount of fiber goes around world 25,000 times. Boyle and Smith - CCD. Central dogma DNA mRNAprotein. The amazing ribosome creates proteins.

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Lecture 11: GPCR pathways

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  1. Lecture 11: GPCR pathways Fain Chapter 4 10/7/09

  2. Kao - high transmission fiber optic cables from pure materials

  3. Fiber optic networks Current amount of fiber goes around world 25,000 times

  4. Boyle and Smith - CCD

  5. Central dogmaDNA mRNAprotein

  6. The amazing ribosome creates proteins

  7. Ada Yonath crystallizes ribosome Small subunit - 32 proteins Large subunit - 46 proteins Geobacillus stearothermophilus - hot springs Haloarcula marismortui - Dead Sea

  8. Homework #5 • Gene duplication • Build a tree (Pasteur) • Think about gene function (OMIM) • Locate genes (Map viewer)

  9. GNAI2 Homework #1: GNA trees GNAI3 GNAI1 GNAT3 Taste Cone Rod GNAT2 GNAT1

  10. Search for gene of interest

  11. Link to chromosome location Click here

  12. Can control which maps are shown

  13. Can remove those you don’t want (rna maps) Highlight items and then click remove Then update with OK

  14. Find chromosomal location of gene - many links

  15. You can zoom in or out to see more detail

  16. Location of GNAT and GNAI GNAT1 GNAI2 3p21 GNAT2 GNAI3 1p13 GNAT3 GNAI1 7q21

  17. Location of GNAI and GNAT

  18. Rest of semester • Individual senses • Fain chapters • Primary literature • Midterm project • Trp channel analysis - next week • Individual project topics • Diversity of one sense across organisms • Signal transduction • Sensory diversity within one organism

  19. The wonders of G protein signaling • Signal amplification • Control, regulation and specificity • Evolution of diversity • Gene expression

  20. Ch4: Metabotropic signal transduction • Indirect link from receptor to channel • Use messenger system • Receptor  G protein  Effector  2nd messenger  Channel  Neural signal • Receptors are G protein coupled • Similar to hormone and neurotransmitter signal transduction mechanisms

  21. Metabotropic sensory transduction Channel Figure 4.1

  22. G proteins activate effectors • Adenylyl cyclase = makes cAMP • Guanyl cyclase = makes cGMP • Phospholipase C = makes DAG and IP3 • Phospholipase A = makes arachidonic acid • Phosphodiesterase = hydrolyzes cAMP or cGMP • 2nd messengers open/close channels • change ion concentration and membrane potential

  23. Diversity of GPCRs • Human genome • 1500-2000 GPCRs (3-5% of genome) • Kinds • Hormone receptors • FSH, Oxytocin, Vasopressin • Synaptic transmitters • Dopamine, opiates, glutamate • Sensory receptors • Olfactory receptors • Visual pigments • Taste receptors for bitter, sweet and AA

  24. Basic GPCR structure • 7 TM regions • Phosphorylation sites on C terminus • G protein binds to C terminus and intracellular loops 2 and 3 Figure 4.3

  25. Basic GPCR structure • 7 TM regions • Phosphorylation sites on C terminus • G protein binds to C terminus and intracellular loops 2 and 3 • Ligand binds either • in membrane • norepinephrine • olfaction • extracellular site • glutamate • GABA Figure 4.3

  26. Xray crystal structure of GPCR Rhodopsin 11-cis retinal Palczewski et al 2000

  27. GPCR phylogeny N=neurotransmitter P=peptides S=sensory Yokoyama and Starmer 1996

  28. G proteins • Ones that interact with GPCR are trimeric - and • Act like switch • Binding site on  for GDP • If exchange GDP for GTP,  becomes activated • Dissociates from 

  29. G protein= • Numbers of different versions of subunits in human genome • 20-30 G • 5 G • 12 G

  30. 1994 Nobel prize in medicine

  31. G GPA Ancient G proteins

  32. G • Gs stimulates adenylate cyclase • includes olfactory

  33. G • Gs stimulates adenylate cyclase • includes olfactory • Gi/Go • Inhibitory and other • Includes vision and taste Transducin gustducin

  34. G • Gs stimulates adenylate cyclase • includes olfactory • Gi/Go inhibits • Includes vision and taste • Gq • Activates PLC

  35. G  and  tethered to membrane  tethered by geranyl geranyl (gg)  tethered by palmitoyl (p)

  36. G bound to GDP is inactive

  37. Activated GPCR activates G protein GPCR    GDP

  38.     +   GTP Get dissociation of G and G GTP binding activates G GPCR*    GDP GTP

  39.   GTP binding activates G Effector + AMP   cAMP Both G and G can activate effector molecules

  40.   GDP GTP hydrolysis inactivates GRecombines with G     + +   GDP Hydrolysis to GDP G will hydrolyze its own GTP slowly GTPase activating proteins speed hydrolysis Regulator of G protein signaling (RGS)

  41. Lichtarge wanted to explain properties of G proteins • How are they kept inactive? • G-G binding • How do they interact with receptors? • GPCR binding • How are they activated? • GDP-GTP binding pocket • How do they interact with effectors? • How are they inactivated?

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