Retinol and Retinaldehyde in the Visual Cycle

Photoexcited rhodopsin activates transducin, a G-protein, which in turn stimulates cyclic GMP phosphodiesterase this leads to closing of an ion channel, hyperpolarization of the membrane, and a decreased rate of neurotransmitter release (Wald, 1968 Stryer, 1986 Chabre and Deterre, 1989). 

The pigment epithelium of the retina receives all- fraws-retinol fromplasma RBP. It is then isomerized to ll-c(s-retinol, which may either be stored as ll-c(s-retinyl esters or oxidized to ll-c(s-retinaldehyde, which is transported to the photoreceptor cells bound to an interphotoreceptor retinoid binding protein. 

Opsin can be considered to be a retinaldehyde receptor protein, functioning in the same way as cell surface receptor G-proteins (Sakmar, 1998). Like receptor proteins, opsin is a transmembrane protein with seven a-helical regions in the transmembrane domain the difference is that opsin spans the intracellular disk membrane of the rod or cone cell, whereas hormone and neurotransmitter receptors span the plasma membrane of the cell. The response time of rhodopsin is considerably faster than that of ceU surface receptor proteins. 

The absorption of light by rhodopsin results in a change in the configuration of the retinaldehyde from the 11 -cis to the all- trans isomer, together with a conformational change in opsin. This results in both the release of retinaldehyde from the Schiff base and the initiation of a nerve impulse. The overall process is known as bleaching, because it results in the loss of the color of rhodopsin. 

The formation of the initial excited form of rhodopsin - bathorhodopsin -depends on the isomerization of 11-cis-retinaldehyde to a strained form of aU- frans-retinaldehyde. This occurs within picoseconds of illumination and is the only light-dependent step in the visual cycle. Thereafter, there is a series of conformational changes leading to the formation of metarhodopsin II. In metarhodopsin II, the Schiff base is unprotonated, and the retinaldehyde is in the unstrained all-trans configuration. 

11-c/s-retinyl esters or oxidized to 11-cis-retinaldehyde, which is transported to the photoreceptor cells bound to an interphotoreceptor retinoid binding protein. 

The conversion of mettirhodopsin II to mettirhodopsin III is relatively slow, with a time course of minutes. It is the result of phosphorylation of serine residues in the protein catalyzed hy rhodopsin kineise. The fined step is hydrolysis to release all-tra/rs-retinaldehyde and opsin. 

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Isomerization of all-rranj-retinaldehyde to 11-cis-retinaldehyde has been shown to be an obligatory event in the function of retinaldehyde in the visual process (Hubbard and Wald, 1952 Wald, 1968). Isomerization of 11-ds- and 13-ciJ-retinol has also been reported to occur in rats both in vivo (Murray et al., 1959 Stainer et al., 1960) and in vitro (Stainer and Murray, 1960). In addition, 13-dj-retinol accounts for approximately 35% of the retinol found in fish liver oils (Robeson and Baxter, 1945, 1947 Hayes and Petitpierre, 1952). Except for the visual cycle, the physiological significance of these isomerization reactions is not yet known. It has been suggested that the occurrence of 13-ds-retinol is not necessarily indicative of a requirement of animals for that isomer, but rather that retinol may naturally occur as a mixture of the cis and trans compounds (Cawley etal., 1948). 

Retinal (retinaldehyde) occurs in significant quantities only in ocular tissue of mammals. Inasmuch as ll-cw and all-Iran isomers of retinal and retinol play important roles in the visual cycle, the separation of geometric isomers of both retinoids is discussed here. All retinoids (and carotenoids) are isomerized by heat and light, so samples should be handled with extreme precautions if information on the original isomer distribution is desired. Because the m-isomers generally have lower molecular extinction coefficients than the -trans forms (Table 1), the presence of large amounts of c -isomers may result in underestimation of retinoid (or carotenoid) quantities. 

The all-rr r-retinaldehyde released from rhodopsin is reduced to all-/n j-retinol and joins the pool of retinol in the pigment epithelium for isomerization to II-c/j-retinol and regeneration of rhodopsin. The key to initiation of the visual cycle is the availability of 11-a j-retinaldehyde, and hence vitamin A. In deficiency both the time taken to adapt to darkness and the ability to see in poor light are impaired. 

In the retinal cells of the eye, vitamin A (all-trans-retinol) is converted into the 11-ds-isomer, which is then oxidised to 11-cts-retinaldehde. In the dark the latter then combines with the protein opsin to form rhodopsin (visual purple), which is the photoreceptor for vision at low light intensities. When light falls on the retina, the czs-retinaldehyde molecule is converted back into the aW-trans form and is released from the opsin. This conversion results in the transmission of an impulse up the optic nerve. The all-frans-retinaldehyde is converted to all-trans-retinol, which re-enters the cycle, thus continually renewing the light sensitivity of the retina (Rg. 5.2). 

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