Ординатура / Офтальмология / Английские материалы / Basic Sciences in Ophthalmology_Velayutham_2009

Fig 13.31

Cation channels require cGMP to be bound to the gate protein for it to remain opened. When the concentration of cGMP is lowered, it dissociates from the gate protein which close and interfere the ion flow. In the dark, there is a potential difference between the inner retina (+ve) and the tips of the outer segment (-ve). The resulting ionic flow is called dark current. In the outer segments of photoreceptors, 2 kinds of protein maintain a constant flow of Na+, Ca++ into the outer segment.

1.Gate protein - allows the passage of Na+, Ca++ into the outer segment. It is maintained in the open state by the cGMP and even Ca++ itself.

2.Na/Ca- K exchange protein - allows a controlled amount of Na+and Ca++ to exit the outer segment in exchange for the inward passage of K+. The function is to maintain the cytoplasmic Ca++ at ~ 400 nm in dark and

at ~ 40 nm in strong light.

On the inner segment of photoreceptors, cation flow is controlled by the actions of Na/KATPase and voltage gated K+ channel protein.

1.Na+/K+ ATPase: maintains an excess of Na+ on the outside of the cell, and K+ inside the cell, the flow is at a slower, controlled rate.

2.Voltage gated K+ channel protein: Selectively extrudes K+ in a voltage dependant manner and maintains a steady flow of K+ outward to contribute to the overall dark current flow of polarization potential ~ 40mv and the release of glutamate neurotransmitter to bipolar cells. When there is continuous interruption in the dark current the change in membrane potential alters the K+ outflow (this is why the protein is called a voltage gated K+ channel) to adopt the cell to continued presence of light. This is a form of light adaptation.

The departing positively charged ions cause the photoreceptor to acquire a net negative charge of ~ 65mv. The cells hyperpolarize. The hyperpolarisation stops the flow of current (i.e., the discharge of the neurotransmitter, glutamate is interrupted) to the ganglion cells of the retina causing the ganglion cells to discharge. This discharge is ultimately transmitted to area of the brain where it is perceived as light (Figs 13.32 and 13.33).

There is amplification of the response in cGMP cascade. One activated rhodopsin can lead to the hydrolysis of 100,000 molecules of c GMP. So, reestablishment of cGMP levels is necessary for further visual acuity of photoreceptor cell. Control of cGMP level is exerted at several points in the cascade.

1)T α (alpha subunit of transducin) is a GTPase. So, it hydrolyses GTP to GDP. Formation of GDP leads to reassociation of T α with Tβλ to form the complete molecule of transducin. Tαβ. GDP which cannot activate

phosphodiesterase.

2)Phosphorylation of opsin by rhodopsin kinase and (C terminal serine and threonine are exposed on bleaching) binding with arrestin inhibits the ability of activated rhodopsin to bind transducin (arrestin combines with rhodopsin only after phosphorylation). Thus, changes in levels of illuminance alter the level of c GMP in rod outer segment.

Fig 13.32: Visual transduction

Fig 13.33

Calcium ions also play a significant role in phototransduction.

1.Calcium calmodulin complex binds to calcium channel protein and decreases its ion permeability. This mechanism acts together with the exchange protein to limit the upper concentration of calcium ions in the outer segment.

2.Calcium ions bind to guanylate cyclase binding protein (GCBP) and inhibit guanylate cyclase. So, when the intracellular Ca++ concentration decreases, guanylate cycalse is activated to produce more cGMP (the reaction catalysed by guanylate cyclase is production of cGMP from GTP). The cGMP will bind to the gate protein and allow more Ca++ to enter the cell through the opened channel.

3.Calcium ions have a direct / indirect influence over voltage gated K+ channel protein of inner segment also.

4.Ca++ bound to recover in the ROS, inhibits rhodopsin kinase. So, the life time of activated rhodopsin is extended (only the activated rhodopsin is phosphorylated by rhodopsin kinase as the serine, threonine amino acids at the C terminus of opsin are exposed on bleaching). Photoreceptors send electrochemical signals to the brain by both direct (cone) and indirect

(coneand rod) synaptic mechanisms (Fig. 13.34).

The cone photoreceptors have many triad synapses on their pedicle (Fig. 13.35). Whereas the rod photoreceptors have a single triad synapse at the end of its presynaptic process (spherule). The constant release of glutamate neurotransmitter is necessary to maintain the synapse in the inactive state i.e., to prevent post synaptic fibres from depolarizing. This is facilitated by the synaptic ribbon apparatus with a RIBEYE protein (synaptic ribbon protein of the eye) as its essential part. It binds to the synaptic vesicles that hold the neurotransmitter and transpose the vesicles to the synaptic membrane at a

Fig 13.34

Fig 13.35: Cone photoreceptor-Triad synapse

rapid rate to facilitate their release. This protein consists of 4 domains with a molecular weight of 120 KD. 2 identicalAdomains are essential for the formation and stabilization of the ribbon structure and 2 identical B domains are responsible for actual binding to the presynaptic vesicles. Vesicle fusion with the membrane occurs in the active zone at the bottom of the ribbon adjacent to the cleft membrane.

Calcium channels also facilitate vesicle fusion and neurotransmitter release by increasing the intracellular calcium necessary for fusion and release and decreasing the glutamate release.

Some biomedical synaptic pathways of the retina:

1.Indirect pathway to adjacent cone photoreceptor.

2.Direct pathway to ganglion cell equivalent to centre on type. GluGlutamate neurotransmitter.

GABAGamma amino butyrate.

Clinical Aspects

•Retinitis pigmentosa (degenerative condition) → disruption of neurotransmission → loss of vision.

•Horner's syndrome -nerve lesions outside the eye → disruption of neurotransmission → loss of vision.

•Parkinson's disease → decreased levels of dopamine in retina (normal 1ng) → loss of contrast sensitivity ability → decreased ability to read. Dopamine

is a NT found in some amacrine cells and interplexiform cells.

Intermediary Metabolism of the Retina

Visual excitation is the unique function of retina and requires energy in the form of ATP derived from metabolism of glucose mainly. Glucose from the retinal capillaries (inner layers) and choroidal (photoreceptor cells) circulation

Fig 13.36

Fig 13.37

Biochemical mechanism behind this is

1.Reaction of aldose reductase ie polyol pathway. As there is no restriction of glucose uptake (retina being not dependent on insulin for glucose uptake) the toxic levels of glucose induce aldose reductase leading to polyol pathway. The end product, Sorbitol of this pathway is an osmotically active component causing the cells to swell and rupture.

2.Diacylglycerol (DAG) synthesized from glyceraldehyde 3 phosphate and dihydroxy acetone phosphate stimulates protein kinase C (PKC) which increases the blood vessels permeability and excessive synthesis of blood vessel membranes (basement membrane thickening). Also PKC induces synthesis of endothelin1 (ET1) which again increases the permeability and blood vessel thickening. Mitogen activated protein kinase (MAP) also have similar effects (Fig. 13.37).