1. How the eye sees Last time Anatomy of the eye Rods and cones Visual receptors Color Vision This time Visual transduction Eye to brain 1

2. Rods and cones have different visual receptors The visual receptors are G protein-coupled receptors seven transmembrane regions hydrophobic/ hydrophilic domains conserved motifs chromophore stably attached to receptor (Schiff’s base Lys296 in TM7) thermostable 2 Nomenclature for visual receptors Receptor == GPCR, opsin Ligand == chromophore, retinal, pigment Receptor bound to ligand == rhodopsin

3. Light hyperpolarizes the cell 3

4. The visual cascade is a G protein-coupled cascade Rhodopsin Gtransducin phosophodiesterase cGMP to GMP close cGMP channels 4

5. Signal transduction in the dark 5

6. Signal transduction in the light 6

7. Negative regulation of phototransduction Rhodopsin Gtransducin phosophodiesterase cGMP to GMP close cGMP channels 7 Closing cGMP channels causes a decrease in Ca2+ Decrease in Ca2+ activates 1. Rhodopsin kinase === deactivate receptor 2. Guanylate cyclase === converts GTP to cGMP === opens cGMP channels Ca2+ independent deactivation also occurs 1. GTPase activating protein

8. Turning off rhodopsin 8 Ca-dependent

9. Turning ON Guanylate Cyclase Guanylate cyclase GTP--- cGMP opens cGMP channels GCAP (less Ca) Phosphodiesterase cGMP--- GMP closes cGMPchannels transducin ENZYME REACTION ACTION on CHANNELS ACTIVATED BY Ca-dependent, Decrease in Ca activates GC 9

10. Turning off the G protein 10

11. Mice without GAP cannot turn off light response quickly no GAP with GAP (wild-type) 11

12. Rods respond to a single photon of light 12

13. Single photon response is very reproducible 13

14. Dark noise is very low 1 rhodopsin/minute 10 8 rhodopins/ photoreceptor 1000 years for all rhodopsins to turn over 14

15. High amplification increases signal size and reliability Rhodopsin Gtransducin phosophodiesterase cGMP to GMP close cGMP channels 1 100 100 100,000 ~1000 15

16. Properties of phototransduction responds to 1 photon of light responses are extremely reliable high amplification of signaling low dark noise 1000s of discs maximize surface area of light detection high concentration and thermostability of rhodopsin means high detection, low noise Photoreceptors are highly specialized to detect light! 16

17. Phototransduction: Differences between rods and cones Rods Cones Very sensitive to light 30x less sensitive to light each rhodopsin activates 30x less G proteins 17

18. Drosophila mutants with abnormal light responses 18

19. The signaling pathway for Drosophila phototransduction Fastest GPCR cascade measured No amplification 19

20. Structure of the eye The Basic Retinal Circuit 1. Receptor Cells (rods and cones) 2. Bipolar Cells 3. Ganglion Cells Connectivity in the retina Back of eye Front of eye 4. Horozontal Cells 5. Amacrine Cells 6. Pigment cells 20

21. View of the retina Ramon y Cajal, Nobel 1906 21

22. Flow of visual information in the retina Vertical Connections Back of eye Front of eye back of eye Photoreceptor Cell---Bipolar Cell---Retinal Ganglion Cell---Brain Horozontal Connections Horozontal Cells- connect photoreceptors and bipolar cells Amacrine Cells- connect bipolar cells and retinal ganglion cells light 22

23. What happens if all rods and cones are killed? 23

24. Unusual retinal gangion cells 24

25. Retinal ganglion cells express melanopsin, are sensitive to light and project to the suprachiasmatic nucleus 25