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Phototransduction – a well studied G-protein cascade

Rhodopsin2 adrenergic receptor

Rhodopsin is a G-proteincoupled receptor (GPCR)

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Visual pigments: seven membrane-spanning loops

Photoreceptors in primates: humans and monkeys

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Spectral Sensitivity

Visual pigments: homologies in amino acid sequences

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AVA-322 : gene for L-opsin - protan defects.AVA-323 : gene for M-opsin - tdeutan defects.

Breakthrough non-surgical intravitreal injection method to deliver genes directly to cone cells at the back of the eye.

Phototransduction

Leads to closure of a cation channel in the plasma membrane. This interrupts the dark current, and hyperpolarizes the rod or cone photoreceptor

The opsin in the outer segments,rhodopsin in rods, catches light and is activated when 11-cis retinal is attached to it

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Photovoltages recorded in monkey rods and cones

The visual cycle – conversion of all-trans retinol(from the blood) to 11-cis retinal in the retinal pigment

epithelium (RPE)

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Biochemical steps in the phototransductioncascade

Phototransduction cascade

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Details of the visual cycle

Retina

RPE FIGURE 3. Schematics of two visual cycles in vertebrate eye. The canonicalRPE visual cycle (left) recycles all-trans-retinol (at ROL) released from rods andcones following a bleach to 11-cis-retinal (11c ROL), which can be used byboth rods and cones for pigment regeneration. The retina visual cycle (right) relies on the Müller cells to recycle all-trans-retinol released from cones to11-cis-retinol, which only cones can move to their outer segments and oxidizeto 11-cis-retinal for regeneration of the pigment. IPM, interphotoreceptormatrix. h, photon of light

Kefalov, JBC 2012

Rod Cone

Wang and Ketalov 2010 PRER The Cone-specific visual cycle

Pigment regeneration, requires RPE for rods.Cone visual cycle includes Mueller cells

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Current flow around photoreceptors

Rod photocurrents:prolonged responses

Cone photocurrents:brief responses

Rods are 70-100 times more sensitive than cones

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RPE cells phagocytose outer segments –entire OS turns over in less than two weeks

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The retina has two blood supplies: outer (PCA) supplies photoreceptorsand inner (CRA) retinal circulation for the rest

Compression – the photoreceptor has a fixed response range. If a steady background uses up some of the range, only the remaining portion will contribute to a flash response

Background effect

Residual stimulus responseFunction on the background

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Calcium dependent mechanisms: feedback in photoreceptors: extends the sensitivity of the response; via GC and cGMP channels open

Tamara et al. 1991 Primate rods – adjustmentof sensitivity

Compressionprediction