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Wing 1 > Retinal Biochemistry & Physiology > Flashcards

Retinal Biochemistry & Physiology Flashcards

1
Q

Ganglion cell axons convey neural signals to terminate in 4 nuclei within the brain – list the nuclei.

A
  • Lateral geniculate nucleus of thalamus – visual perception
  • Superior colliculus of midbrain – control of eye movements
  • Pretectal area of midbrain – control of pupillary light reflex
  • Suprachiasmatic nucleus of hypothalamus – control of diurnal rhythms and hormonal changes
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2
Q

Discuss the functions of Muller cells.

A

Regulation of the extracellular space

a. Potassium
- Light-evoked neuronal activity causes an increase in extracellular K+ concentration in the synaptic layers
- Müller cell regulation of K+ is important since fluctuations alter neuronal excitability
- “K+ siphoning”: K+ moves from high to low concentrations via potassium channels in Müller cells. Certain types of potassium channels are found in Müller cell end-feet facing the vitreous and in membranes of processes in contact with blood vessels. Vitreous humor and blood vessels may serve as potassium ‘sinks’.

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3
Q

Muller cell function: CO2 and pH regulation

A
  • Contain sodium-bicarbonate co-transporter

- Convert CO2 (from retinal neuron aerobic pathways) to bicarbonate via carbonic anhydrase to maintain extracellular pH

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4
Q

Muller cell function: Neurotransmitter uptake and conversion

A
  • Regulate extracellular levels of glutamate and GABA
  • Contain uptake systems and degradative pathways
    • Müller cells express glutamate/aspartate transporter (GLAST)
    • Inactivate glutamate by conversion to glutamine
    • Glutamine is transported to neurons as a precursor for synthesis of glutamate & GABA
    • Uptake and clearance of neuronal synaptic glutamate prevents neurotoxicity
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5
Q

Muller cell function: Glucose metabolism

A
  • Glucose is transported from blood to Müller cells via a glucose transporter
  • Converted into glycogen - Müller cells only site for glycogen storage in the retina
  • Converted into lactate/pyruvate via glycolysis
  • Lactate/pyruvate supplied to retinal neurons for their oxidative metabolism
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6
Q

Muller cell function: Visual pigment recycling

A

in studies of cone-dominant chicken eyes, Müller cells contain an alternate pathway for regeneration of cone visual pigment

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7
Q

List the functions of the RPE as it relates to their close association to the outer segments of photoreceptors.

A
  1. Blood-retina barrier (blood-ocular barrier) –tight junctions inhibit movement of water via a paracellular route. Barrier contributes to immune priviledge of the eye.
  2. Selective transport of metabolites & ions between blood & subretinal space; “gatekeeper” to the retina
  3. Vitamin A esterification, storage and transport
  4. Synthesizes extracellular molecules
  5. Phagocytosis of outer segment discs
  6. Contains hydrolytic enzymes to digest discs
  7. Absorption of scattered light
  8. Secrete growth factors and cytokines that are important in development & maintenance of retina
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8
Q

What is the function of pigment epithelium-derived growth factor?

A

Pigment epithelium-derived growth factor (PEGF): a neurotrophic factor, protects against hypoxia- and glutamate-induced apoptosis and an anti-angiogenic factor.

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9
Q

Describe the interphotoreceptor space (boundaries, originated from?).

A

Subsensory retinal space (SSRS) = subretinal space

  1. Strategic interface between RPE and retina
  2. Remnant of the optic ventricle
  3. Boundaries: RPE tight junction. External limiting membrane = intercellular junction between Muller cells & photoreceptors
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10
Q

Discuss the interphotoreceptor matrix

A
  1. Bathes 4 cell types: Müller cell, RPE, Rod & Cone photoreceptors
  2. Major role in biochemical and physical interactions between the cell populations
    a. High fluxes of water, oxygen, bicarbonate, inorganic ions, sugars, amino acids & retinoids
  3. Rapid turnover by RPE and photoreceptor endocytosis
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11
Q

function of interphotoreceptor retinoid binding protein, which cell synthesizes it, why is it necessary for retinoid trafficking?

A

a) Secreted by photoreceptors into IPM
b) Trapped within the IPM: IRBP is larger than the exclusion limit of the photoreceptor/Müller cell zonulae adherens junctions (ELM)
Retinoid trafficking - Transports II-cis retinal and all-trans retinol
- Solubilizes retinal and retinol, which are insoluble in water
- Protects retinal and retinol against oxidative and isomeric damage

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12
Q

Outer segment: In rod photoreceptors most of the protein in outer segment is used to form ______________________.

A

Rod photoreceptor

1) Rod opsin: protein component of rod visual pigment. Comprises ~80% of OS protein.

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13
Q

Discuss the significance of polyunsaturated fatty acids in photoreceptor membranes.

A

Polyunsaturated fatty acids contribute to fluidity of disc membrane

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14
Q

List the major polyunsaturated fatty acid (an omega-3 fatty acid) in rod outer segments.

A

Docosahexaenoic acid (DHA) - an omega-3 fatty acid

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15
Q

Inner segment: List the general functions of the ellipsoid and myoid regions

A

Ellipsoid: mitochondria
Myoid: Endoplasmic reticulum (ER), Golgi apparatus
Function: High oxygen consumption and glycolysis at very high rates, synthesizes components for outer segments.

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16
Q

In general, describe disc morphogenesis

A

Photoreceptors are post-mitotic, terminally differentially cells. The process of disc renewal is coordinated with shedding and degradation of the discs, allowing the outer segment to maintain a constant length throughout adult life.

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17
Q

What is the significance of membrane renewal?

A

Membrane renewal allows the photoreceptor to replace old or damaged outer segment discs, thus maintaining a population of functional cells.

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18
Q

List the function of the connecting cilium.

A
  1. Connects inner segment and outer segment
  2. Intracellular transport along the connecting cilium
  3. Bidirectional trafficking of proteins occurs through the connecting cilium
  4. Proteins and lipids synthesized in inner segment move along connecting cilium to OS
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19
Q

Disc Shedding: Formation of new discs is balanced by?

A

phagocytosis of outer segment tips by RPE, maintaining constant length of the outer segment.

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20
Q

Describe the general process of disc shedding

A

a. Recognition and binding of outer segments receptors in RPE plasma membrane
b. Phagocytosed discs are contained in vesicles called phagosomes
c. Lysosomes release hydrolytic enzymes to digest the material
d. Essential fatty acids are recycled; waste products are transported across the basal RPE membrane.
e. Each RPE ingests and digests up to 4000 discs/day. Membranous material may be retained in the RPE and contribute to formation of lipofuscin.

21
Q

Why are the outer segments susceptible to oxidative damage?

A
  1. High oxygen environment (choriocapillaris is a rich source of oxygen)
  2. High concentration of polyunsaturated fatty acids- mainly DHA
  3. Light stimulation (photooxidation)
22
Q

What is the general action of free radicals on cell components?

A

a. Membrane damage
b. Phospholiipid peroxidation
- Free radicals attach PUFAs in lipids
- Induces a chain reaction of lipid peroxidation that breaks down membranes
- Damage spreads from absorbing molecule to other molecules

23
Q

List defense mechanisms as presented in class.

A

a. Absorption of light: RPE contains melanin
b. Filtering of light: PRs contains xanthophylls
c. Antioxidants (direct free radical scavengers): Beta-carotene, vitamin C and E
d. Enzymes: superoxide dismutase, glutathione peroxidase, catalase

24
Q

Describe the components of visual pigment.

A

Visual pigment: chromophore (11-cis-retinal) + opsin

25
Q

List the structure of the chromophore

A

11-cis-retinal
-a light-sensitive carotenoid derivative of Vitamin A
same chromophore for ALL visual pigments
Protein (opsin)
-an integral membrane protein (glycoprotein)
-7 alpha-helices traverse the disc membrane (transmembrane protein)
-binding pocket for 11-cis-retinal
-different opsin for each class of visual pigment (scotopsin, photopsin)

26
Q

What is the linkage that binds the chromophore to the opsin?

A

-Schiff-base linkage forms between retinal & epsilon amine of a lysine amino acid of the opsin

27
Q

What effect does the Schiff base linkage have on the absorption wavelength of the chromophore

A

due to the protonation of the Schiff base, the absorption wavelength of the chromophore shifts from the UV to visible region of the spectrum

28
Q

What component of visual pigment is responsible for the unique spectral sensitivity curve of each class of visual pigment?

A

the opsin is responsible for the spectral sensitivity curve of each class of visual pigment (the peak wavelength that a visual pigment absorbs)

29
Q

Is the chromophore synthesized in the photoreceptor?

A
  • No, the RPE stores and releases 11-cis retinal to the photoreceptors
30
Q

List 3 effects of vitamin A deficiency.

A
  • decreased visual pigment
  • decreased disc production (night blindness)
  • keratinization: of squamous epithelium, cornea opacifies (squamous metaplasia)
  • xerophthalmia
31
Q

Describe the orientation of visual pigment in the disc membranes that serves to maximize absorption of the photon.

A

Chromophore lies in a plane perpendicular to the long axis of the photoreceptors

b. Visual pigment transverses entire width of disc membrane
- Transmembrane protein
- Alpha helices traverse lipid bilayer seven times
c. Opsin can rotate and translate within disc membrane (membrane very fluid)

32
Q

Compare the resting potential of a typical neuron to that of a photoreceptor.

A

Resting potential of neuron
a.Hyperpolarized (internal negative charge)
b.-70 mv in most resting neurons
Rod photoreceptors has a negative resting membrane
potential but less negative (-40 mV) than in many other neurons

33
Q

Describe the dark current.

A

cGMP-gated cation channels in
plasma membrane of outer segment
- Cation channels are OPEN when the ligand, cGMP, binds to the channel
- Open in the dark (resting state)
- Inward flow of Na+, Ca++, Mg++ across the outer segment membrane into photoreceptor
- Inward dark current is primarily due to Na+ influx- sustains steady release of neurotransmitter in the resting state

34
Q

What ion is primarily responsible?

A
  • Na+
35
Q

Describe the features of a rod photoreceptor in the dark (resting state).

A
  • photoreceptor is relatively depolarized
  • resting potential of outer segment in the dark is -40 mV
  • relatively depolarized state sustains steady release of NT
36
Q

List the channels/exchangers that are responsible for the movement of Na+ and Ca++ into and out of the cell.

A
  • cGMP-gated cationic channels
  • Na/Ca,K exchanger
  • Na+/K+ ATPase on plasma membrane of outer segment membrane of inner segment
37
Q

What effect does a photon of light have on visual pigment?

A
  • photon causes a photoisomerization of the chromophore portion of visual pigment.
  • the activated visual pigment starts a cascade of events that leads to closure of the cGMP-gated cation channels (Na+) on the plasma membrane and hyperpolarization
38
Q

Describe the general sequence of events that occurs during phototransduction.

A

-Phototransduction: the process by which light is converted to an electrical neural signal
1. Activation of rhodopsin
-photon causes photoisomerization and 11-cis-retinal is isomerized to all-trans retinal
-schiff base linkage is deprotonated
-formation of Metarhopdopsin 2
-conformational change in opsin creates binding site for transducin
2. Activated form of rhodopsin (R* = metarhodopsin 2)
-R* triggers enzymatic cascade
-R* interacts with transducin
activated transducin binds to (PDE6*) - hydrolyzes cGMP
- cytosolic cGMP levels dec.

39
Q

What is the activated form of rhodopsin?

A
  • Metarhodopsin 2
40
Q

What effect does light have on cyclic nucleotide activity in the outer segments?

A
  • with decreased cGMP levels in cytoplasm, cGMP dissociates from cGMP-dependent (ligand-gated) cation channels on plasma membrane
  • cGMP-gated cation channels CLOSE
41
Q

What is the internal (second) messenger of phototransduction?

A

Guanosine nucleotide as 2nd messenger (internal messenger), acts as the “go-between” from the discs to the outer segment membrane channels
- cGMP binds to cation channels on plasma membrane

42
Q

What happens to intracellular calcium levels following light stimulation of the rod photoreceptor?

A
  • dark current is reduced: Na+/Ca2+/Mg2+ no longer enter
  • however light does not affect the activity of Na+/Ca2+, K+ exchanger in plasma membrane of outer segment of Na+/K+ pump in the inner segment
43
Q

Summarize the features of a rod after it has been stimulated by light.

A
  • dark current reduced
  • hyperpolarized
  • decreased neurotransmitter release
44
Q

Describe how the effect of light differs in cones compared to rods

A

Differences between rod and cone phototransduction

  • single-photon response in cones is 100-fold smaller than that in rods
  • cone response to single photon is not detectable (unlike rods)
  • cone response shows faster response kinetics (due to configuration of cone outer segment)
  • cones adapt to light more effectively than rods
  • regenerate chromophore in muller cells
45
Q

Describe the two steps that are responsible for the amplification of the phototransduction cascade.

A
  1. 1 activated rhodopsin (R*) activates up to 500 transducin molecules
  2. 1 activated PDE molecule causes hydrolysis of up to 2000 cGMP molecules
46
Q

Describe the visual (retinoid) cycle involving photoreceptors & RPE.

A
  1. Recycling of the chromophore by RPE – rods & conesa.
    11-cis-retinal isomerized to all-trans retinal, must be continuously regenerated for the retina to: be responsive to light and maintain vision.
    b. Photoisomerized chromophore only transiently activates the opsin and all-trans-retinal is hydrolyzed and released from the opsin
    c. All-trans-retinal is converted to all-trans-retinol, exits rod and is sent to RPE
    1) (IRBP) protects retinoids (retinol, retinal) from degradation & isomerization as it travels across the aqueous medium of the IR matrix to the RPE
    2) Water-insoluble all-trans retinol in the RPE is bound to cellular retinol-binding protein (CRBP) – binds it within RPE and protects against oxidation or isomerization.
    d. RPE converts all trans-retinol to 11-cis-retinal, which binds (CRALBP) for movement within the RPE.
47
Q

At the end of the retinoid cycle, 11-cis retinal is

A

now available to photoreceptors to incorporate into new visual pigment molecules.

48
Q

How are Muller cells involved in recycling of chromophore in cones?

A

1) Intense light exposure activates (bleaches) large quantities of visual pigment
2) Cones need to rapidly recycle chromophore and regenerate visual pigment
♣ Cones regenerate their visual pigment faster than rods
♣ Allows cones to restore their light-sensing abilities much faster than rods (remain functional and are not saturated even in very bright light)
♣ Allows cones to extend their functional range under bright light.

Wing 1 (1 decks)

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