Phototransduction, Color Vision, and Blindness

A light signal only goes through which cells in the retina?

photoreceptors -> bipolar cells -> ganglion cells -> optic nerve -> visual cortex (area 17 of the cortex)

Are rods or cones more abundant?

rods

Do rods or cones have a double membrane?

rods

What is the function of rods?

vision in dim light

What is the function of cones?

color vision, rapid motion detection

Are rods or cones more sensitive?

rods

What is 11-cis retinal a derivative of?

vitamin A

Mutations of rhodopsin can cause which diseases?

- autosomal dominant retinitis pigmentosa (ADRP)

- congenital stationary night blindness (CSNB)

What percentage of the protein in the rod's disks is rhodopsin?

85%

In the dark, what is the membrane potential of the rod?

~-40 mV

In the dark, is glutamate released or inhibited from the rod?

released

Is more energy demanded from rods cells in the light or dark?

dark

Where is the N-terminus of rhodopsin located? C-terminus?

- N-terminus: disk lumen

- C-terminus: cytoplasm

After 11-cis retinal and opsin join to form rhodopsin, what happens when a photon is absorbed by rhodopsin?

11-cis retinal photoconverts to all-trans, which changes rhodopsin's conformation from bent to straight

What happens immediately once rhodopsin is activated?

active rhodopsin (R) binds and activates its G-protein transducin (Gt)

What does Gt* activate? What does this activation act as a catalyst for?

- Gt activates the enzyme cGMP-specific phosphodiesterase (PDE6->PDE6)

- PDE6* catalyzes hydrolysis of cGMP to GMP

What do decreased amounts of cGMP do?

close CNG-gated cation channels

What happens once CNG-gated cation channels are closed?

Na+ ions can no longer enter the cell, photoreceptor hyperpolarizes (-70mV)

Hyperpolarization of the cell (change in membrane potential) causes which channels to close?

voltage-gated calcium channels close

Once voltage-gated Ca2+ channels have closed and a decreased amount of Ca2+ is entering the cell, what happens to glutamate? What does this do to the post-synaptic bipolar cells?

- decrease in glutamate concentration (near 0)

- can either excite or inhibit post-synaptic bipolar cells

List the steps of phototransduction (summary)

1) 11-cis retinal + opsin -> rhodopsin

2) rhodopsin absorbs a photon, 11-cis retinal converts to all-trans, rhodopsin changes conformation from bent to straight

3) R binds and activates Gt -> Gt

4) Gt activates the enzyme cGMP-specific phosphodiesterase (PDE6->PDE6)

5) PDE6* catalyzes hydrolysis of cGMP->GMP

6) decreasing cGMP closes CNG-gated cation channels

7) Na+ cannot enter cell, photoreceptor hyperpolarizes (no action potential)

8) change in membrane potential causes voltage-gated Ca2+ channels to close

9) decrease in [Ca2+] entering cell

10) decrease in [glutamate] (near 0) -> inhibit or excite post-synaptic bipolar cell

When the CNG-gated cation channels close, is the Na+/Ca2+-K+ exchanger (NCKX1) affected?

no

When the CNG-gated cation channels close, is the Na+/K+ ATPase still active?

yes

What is the structure of PDE6?

- two large catalytic subunits: PDE6a, PDE6b

- two small inhibitory subunits: PDE6g

To initiate the recovery phase, what occurs once [Ca2+] levels decrease?

- rhodopsin kinase phosphorylates rhodopsin (serines near C-term)

- arrestin binds to opsin, preventing rhodopsin from activating Gt

What is the rate-limiting step of the recovery phase?

GAP complex proteins catalyze Gt's GTP->GDP via an enzyme in the complex called RGS9-1 (inactivates Gt)

Once Gt is inactivated, what happens to PDE6?

PDE6g rebinds to PDE6ab

Decreased [Ca2+] provides a feedback signal to restore cGMP levels. What is Ca2+ then released from and what does it then do?

Ca2+ is released from Guanylate Cyclase Activating Proteins (GCAPs), causing them to activate Guanylate Cyclase (GC). GC restores resting levels of cGMP.

What happens once resting levels of cGMP are restored?

Na+/Ca2+ channels reopen

What is the function of the GAP complex?

to accelerate the intrinsic GTPase activity of Gt-alpha subunit to increase the rate of GTP hydrolysis to GDP

What are the components of the GTPase Accelerating Protein (GAP) complex?

- RGS9-1

- R9AP

- Gb5

In the adaption phase, what does Ca2+ bind to?

Ca2+ binds to recoverin (Rcv) which inhibits rhodopsin kinase and prevents rhodopsin inactivation

Does binding of Ca2+/Calmodulin to the cG-gated channel reduce or enhance the affinity of the channel for cGMP? Does it take more or less cGMP to keep the channel open?

- reduce

- takes more cGMP to keep the channel open

What does repeated recovery do to photoreceptors?

it causes cells to desensitize, allowing them to adjust to an increase in light intensity

What is rhodopsin bleaching?

11-trans retinal must convert to 11-cis retinal to be recycled. without opsin, the pigment cannot do much

What percentage of the cones are red, green, and blue?

- red: 64%

- green: 32%

- blue: 2%

Where does the isomerization of retinal occur?

- cones: in Muller cells

- rods: in RPE

Which pigments in the visual spectrum have significant overlap?

red and green

What are the long, medium, and short wavelength photo pigments?

long (L): more towards red

middle (M): in the middle

short (S): more towards UV

What is color blindness caused by?

X-linked mutation in either the long, middle, or short wavelength-sensitive visual photo pigments, or a mutation on chromosome 7

Which type of color blindness is a trait found on the X chromosome?

red/green (M/L) color bindness

Which type of color blindness is a trait found on chromosome 7?

blue/yellow (S) color blindness

What is monochromacy/achromatopsia?

occurs when two or all three of the cone pigments are missing and color and bright light vision is reduced to one dimension -> total color blindness

What is dichromacy?

occurs when only one of the cone pigments is missing and color is reduced to two dimensions -> partial color blindness (red/green, blue/yellow)

What is the inheritance pattern of color blindness in males?

hemizygous (X'Y)

What is the most common type of color blindness?

red/green color blindness

What are the four types of red-green color blindness?

1) deuteranomaly

2) protanomaly

3) protanopia

4) deuteranopia

What do -opia and -anomaly color blindness conditions mean?

-opia: non-functional

-anomaly: affected but still functional

What is deuteranomaly?

- most common type -> makes green look more red

- mild

What is protanomaly?

- makes red look more green and less bright

- mild

What is protanopia and deuteranopia?

both make you unable to tell the difference between red and green at all

What are the two types of blue-yellow color blindness?

- tritanomaly

- tritanopia

What is tritanomaly?

makes it hard to tell the difference between blue and green, and between yellow and red

What is tritanopia?

makes you unable to tell the difference between blue and green, purple and red, and yellow and pink. also makes colors look less bright

What other conditions is total color blindness associated with?

- reduced VA from infancy

- photophobia

- nystagmus

What is total color blindness caused by? Which genes often have a mutation?

- result of absent or nonfunctioning retinal cones

- most often caused by a mutation in the CNGB3 gene (~50%)

- other genes: CNGA3, GNAT2, PDE6C, PDE6H, ATF6

What does classic achromatopsia result from? What does this gene code for?

- results from a complete loss of CNGB3 function

- CNGB3 encodes for the beta subunit of the cone cyclic nucleotide-gated cation channel in cone photoreceptor plasma membranes

Is CNGB3 expressed anywhere else in the body besides cones?

no

Are there any cures or treatments for color blindness? What are they?

no cure, but there are some treatments for NON-inherited color blindness:

- cataract surgery if problem is from cataracts

- special contact lenses and glasses to help people tell the difference between colors

- gene therapy potentially...

Special filters in glasses can help patients with which type of color blindness to enhance color vision?

red-green color deficiency "anomalous trichromacy"

The AREDs Clinical Trial of the NEI found that some nutritional supplements helped in delaying AMD progression. What nutrients were they?

zinc, beta-carotene, and vitamins C and E

What was the first supplement found to be effective in treating RP?

vitamin A

What are the two categories for electronic prosthetic devices for sight restoration?

1) brain (cortical) electronic implants

2) retinal implants

How do Cortical Visual Prosthesis (CVP) systems work?

- images captured by a camera implanted into a pair of glasses

- images are then processed by an external pocket processor to produce stimulation transferred to the implants (in visual cortex) via a transmitter coil

What is the retinal prosthesis concept?

- uses electrical stimulation to bypass defective or dead photoreceptors and stimulate remaining viable, non-photoreceptor cells of the retina

- image data from an external camera is wirelessly transmitted to the implant which stimulates electrodes in an array on the retina to produce vision

What is the Argus II system?

- retinal prosthesis that has 60 electrodes, allowing for detection of light and movement, but not image details

- smaller, designed to last a lifetime

What are the current limitations with retinal prosthesis?

electrodes produce heat, which can melt the retina

Where does the isomerization process occur on the 11-cis retinal molecule?

- occurs on carbon 11-12 (single rotational shift which changes conformation from bent to straight)

What is the counterion of rhodopsin?

glutamate