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Lecture #17

Lecture #17. The visual cycle + eye disease 4 /2/13. Spatial resolution – last time B/W did have highest resolution. Patrick – what do photoreceptors see?. Visualization. t an θ and θ. 0.1. 10. EEEEEEEEEE.

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Lecture #17

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  1. Lecture #17 The visual cycle + eye disease 4/2/13

  2. Spatial resolution – last timeB/W did have highest resolution

  3. Patrick – what do photoreceptors see? • Visualization

  4. tan θ and θ 0.1 10

  5. EEEEEEEEEE • Calculate the image size on your retina for one line of the small E in the front of the room • Write the image size of one line on the board according to where you are sitting • How many receptors does one line of the small E cover on your retina?

  6. Next few lectures • Visual cycle - today • Much of this pathway has been identified through disease studies • Visual cycle in rods • Visual cycle in cones • Eye diseases – next 3 lectures • Retinal disease • Other diseases (glaucoma, cataracts etc) • Treatments

  7. Visual cycle: recycling 11-cis retinal through isomerization and pigment regeneration

  8. George Wald showed 11-cis retinal isomerizes to start vision

  9. G protein pathway in rod disc Rhodopsin G protein R + hvgR* Rhodopsin absorbs photon g excited R* + GαβγgR* + Gα*-GTP + Gβγ Rhodopsin activates G protein

  10. R* shutoff: phosphorylation and arrestin binding Inactive R has all trans retinal bound to it – need to regenerate 11-cis retinal and reform visual pigment

  11. Photoreceptors at the very back of the retina next to retinal pigment epithelium (RPE) Pigment epithelium http://webvision.med.utah.edu/

  12. Some facts about pigment regeneration after pigment absorbs light (bleached)

  13. Phototransduction: 11-cis + photon = all transVisual cycle: all trans + enzymes = 11-cis Visual cycle  Phototransduction

  14. Retinal pigment epithelium (RPE) - plays a big role in 11-cis retinal regeneration in rods Retinal dissociates from opsin, diffuses out of photoreceptor, goes to RPE, gets regenerated and comes back

  15. O C R H Both 11-cis and all-trans retinal are isomers of the same aldehyde : retinaldehyde 11 11 R-CHO

  16. O C R H Retinoid biochemistry • Aldehyde RCHO -al • Alcohol ROH -ol • Ester R-CO-O-R’ R OH O R’ C R O

  17. Opsin + retinal = Schiff base Schiff base is a carbon nitrogen double bond, C=NR3 In the case of rhodopsin, the N comes from the lysine and C comes from the retinal + X-(CH2)4NH2 Lysine

  18. Schiff base Schiff base can often be protonated NH+

  19. membrane Visual pigment =opsin + retinal In rod, visual pigment is called rhodopsin 11-cis retinal

  20. 11-cis in retinal binding pocket

  21. Phototransduction occurs in retina: rods and cones

  22. Phototransduction occurs in retinaVisual cycle occurs in retina and RPE

  23. Retinoids (Bound to opsin)

  24. Moving retinoids around takes chaperones They protect retinoids from oxidation and isomerization They help transfer fat soluble retinoids across aqueous layers

  25. Moving retinoids around takes chaperones IRBP - interphotoreceptor retinoid binding protein CRBP - cellular retinol binding protein CRALBP - cellular retinaldehyde binding protein

  26. Slightly different version

  27. First steps to retinal regeneration Rod Disc ABCR = ATP binding cassette transporter ABCR binds to all trans retinal (RAL) and helps it diffuse out of discs This leaves free opsin which is ready to make new visual pigment Apo-protein = protein without prosthetic group which is needed for its function

  28. First steps to retinal regeneration Rod Disc All-trans retinol dehydrogenase (RDH) converts all trans retinal to all trans retinol

  29. Retinal(dehyde)  retinol H H Note: all-trans-ROL=Vitamin A!! C-OH RDH12 H C=O

  30. Moving retinoids around takes chaperones IRBP - interphotoreceptor retinoid binding protein

  31. Transport of retinol to RPE Interphotoreceptor retinol binding protein (IRBP) helps transport all-trans retinol to the RPE RPE

  32. Moving retinoids around takes chaperones In RPE, CRBP binds retinol 100x greater CRBP = cellular retinol binding protein

  33. Conversion of all trans retinol LRAT = lecithin retinol acyl transferase Converts all trans retinol to all trans retinal ester Works best on retinol bound to CRBP

  34. Convert to ester LRAT = adds acyl group O

  35. Isomerization IsomeraseRPE65 converts all trans retinyl ester to 11 cis retinol RPE65 is 65 kilodaltonprotein which occurs in RPE RGR - retinal G protein coupled receptor is enzyme that may help in isomerization

  36. Forms 11-cis retinal Retinal dehydrogenase converts 11-cis retinol to 11-cis retinal CRALBP is cellular retinal binding protein Can bind ROL or RAL to help move either Can store 11-cis ROL as ester till needed.

  37. Conversion RDH5

  38. Conversion RDH5 RDH12 In RPE In rod

  39. Summary

  40. IRBP takes 11cis-RAL back to photoreceptor RPE65 Reforms the active visual pigment

  41. Visual cycle in rods • Needs RPE • All trans retinol leaves retina and goes to RPE to be regenerated • Without RPE, no isomerization and no visual pigment regeneration • Takes time for retinal to be transported around so slow process

  42. Retinal regeneration in cones • Cones do NOT require RPE • Isolated retina can regenerate pigment • Cones can use 11 cis retinol to regenerate pigment • If add 11 cis retinol, cones can convert this to 11 cis retinal and regenerate pigment • In bright sun, need more 11-cis than can regenerate with known rod visual cycle

  43. Cone visual cycle is different - uses Muller cells

  44. Cone visual cycle

  45. Cone visual cycle Don’t yet know the isomerase

  46. Use ARAT to form retinal ester

  47. BIG DIFFERENCE - 11cis ROL goes back to cone outer segment where it is converted to 11-cis RAL

  48. Why have two visual cycles in same retina? 11-cis RAL to rods 11-cis ROL to cones

  49. Theories • Deficiency / survival - independence of rod and cone pathways • Sensitivity - so rods can detect lower levels of light • Energy needs of cones are greater • Cones / rods process different information • Cones function at hi light, rods at low

  50. Cone pathway • Cones work at higher light levels • Opsin bleached more rapidly • Cone visual cycle is 20 times faster • Muller cells send 11-cis retinol to cones • Rods can’t convert this so can’t “steal” from cone pathway • Important for rod dominated retina • 20-100x more rods than cones

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