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Lecture 20 : Olfaction II

Lecture 20 : Olfaction II. 11/11/09. For next week. See web site Background - 1 pg. Topics. Diversity of ORs Which receptors detect which odorant? Olfactory signal transduction How does it compare to visual transduction? Multiple olfactory organs

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Lecture 20 : Olfaction II

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  1. Lecture 20 : Olfaction II 11/11/09

  2. For next week • See web site • Background - 1 pg

  3. Topics • Diversity of ORs Which receptors detect which odorant? • Olfactory signal transduction How does it compare to visual transduction? • Multiple olfactory organs Nose vs VNO : How do the receptors compare? • Signal transduction How do pathways compare?

  4. How do we understand receptor specificity?

  5. Functional response of rat I7 receptor I substitutions II chain length III/IV degree sat III/V side chain Response R>G>B

  6. Functional group Compare response of control cells vs ones containing I7 receptor

  7. Length and saturation C8 is best though receptor responds to others too

  8. Effect of substitutions

  9. Expressing olfactory receptors • Ways to express genes • Make transgenic animals • Express in Xenopus oocytes • Ideal to do in cell culture • Ways to probe • Intracellular recording of one cell • Pull off patch of membrane • Ca+2 imaging

  10. Matsunami’s lab - cell culture

  11. Cofactors for OR expression

  12. Olfactory signal transduction Odorant in activates receptor activates Golf activates AC makes cAMP

  13. Monitor cell response with luciferase CRE luciferase CRE = cAMP response element luciferin Odorant in -> cAMP -> luciferase + luciferin = LIGHT

  14. Screen panel of 96 receptors

  15. Screen panel of 96 receptors Flow reactant 1 and determine which receptors respond

  16. Screen panel of 96 receptors Flow reactant 2 and determine which receptors respond Map out response space

  17. OR response • Map out response to range of chemicals and odorant levels • Different receptors respond to different ligands

  18. Variation in human sensitivities

  19. Human perceptual variation • Androstenone is odorous steroid • Derived from testosterone • Human response varies • Offensive = Sweat / urine • Pleasant = sweet, floral • Odorless

  20. OR7D4 receptor is sensitive for androstenone/androstadienone Screened 335 OR’s (85% of known ORs!)

  21. Human allelic variation in OR7D4 • Search SNP database and seq in 391 test subjects - variation at 2 AA • R88W T133M • Two common genotypes RT or WM • Normal (RT) 0.786 • WM 0.157 • P79L 0.04 • S84N 0.013

  22. WM allele much less sensitive than RT allele RT vs WM allele

  23. Common alleles affect sensitivity

  24. Rare alleles have opposite effects P79L not sensitive S84N very sensitive Chimp even more sensitive

  25. Genotype affects perception

  26. Human genotype affects threshold sensitivity

  27. Olfactory signal transduction

  28. Olfactory signal transduction

  29. Comparison of visual and olfactory activation

  30. Comparison of visual and olfactory activation

  31. Olfactory signal recovery 1. OR* gets phophorylated and binds arrestin 2. PDE turns cAMP into AMP This decreases cAMP binding to channel Channel closes #1 #2

  32. Olfactory signal recovery Adaptation CaM-Ca+2 binds to channel and decreases cAMP binding CaM-kinase phosphorylates PDE which acts faster CaM kinase phosphorylates AC which acts slower

  33. Phototransduction recovery

  34. Comparison of visual and olfactory deactivation

  35. Multiple olfactory cues • Need to detect general odors • Food, environment • Species specific odors • Pheromone = • pherein (to carry or transfer) + • horman (to excite) • Volatile (broadcast info) or non-volatile (individual specific)

  36. Organs for detecting compounds • Olfactory • Vomeronasal • Trigeminal

  37. Multiple olfactory organs

  38. Mouse olfaction Main olfactory epithelium (MOE) Expresses olfactory receptors OR (1300) and Trace amine associated receptors TAAR Project to main olfactory bulb (MOB) Brennan and Zufall 2006

  39. Mouse olfaction Vomeronasal organ (VNO) Expresses two types of receptors: V1R (137) and V2R (60) Project to Accessory olfactory bulb (AOB) Brennan and Zufall 2006

  40. VNO Two kinds of receptors which differ in location and projection Response to putative pheremones

  41. Comparison in rodents

  42. V2R’s similar to mGlu receptors

  43. Diversity of GPCRs Bargmann 2006

  44. Comparison of pathways

  45. G • Gs stimulates adenylate cyclase • includes olfactory • Gi/Go • Includes vision and taste • Gq • Activates PLC V2R Vision/taste V1R OR

  46. Comparison of pathways

  47. Comparison of pathways

  48. VNO mystery #1 • Are vomeronasal receptors for species specific communication?

  49. OR phylogeny

  50. VNO receptors Species specific as if they evolved for intra-species communication

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