Visual Cycle in Retinal Rods
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Visual Cycle in Retinal Rods

Vitamin-A (all-trans-Retinol) is a vital and essential micronutrient in the human diet and is required for multiple physiological processes, ranging from vision to embryonic development. ‘Vitamin-A’ means a group of substances (Retinol, Retinyl Esters and Retinal) with defined biological activities. Further, there are certain metabolites of Vitamin-A, such as all-trans and cis-isomeric Retinoic Acids, that perform some, but not all, of the biological functions of Vitamin-A; they are incapable of being metabolically converted into Retinol, Retinal, etc. The main dietary sources of Retinol are Retinyl Esters from meat, and Carotenoids, such as Beta-Carotene, from plant tissue (Ref.1). Dietary Vitamin-A gives rise to a variety of active metabolites, collectively known as Retinoids (also known as Vitamin-A Analogues). Retinoic Acid and some of its isomers and derivatives, together with a number of structurally modified Retinoids, control cell differentiation in many epithelial tissues in order to prevent Metaplasia. Some of the Vitamin-A derivatives are used in the treatment of Keratinization disorders and cannot substitute for Vitamin-A; indeed some of them even act as Vitamin-A antagonists and the term ‘Retinoids’ is widely employed for such compounds. Infact ‘Retinoids’ are compounds used collectively for both natural forms and synthetic analogues of Vitamin-A that are capable of controlling epithelial differentiation and preventing the development of Cancer without possessing the full range of activities of Vitamin-A and therefore can also be termed  as ‘Retinoate Analogues’. There are six known isomers of Retinol: all-trans, 11-cis, 13-cis, 9,13-di-cis, 9-cis, and 11,13-di-cis, with the all-trans form being predominant under most physiological situations (Ref.1 & 2).

Vision in all species begins with the absorption of light by Rhodopsin (or Red Opsin); initiating the heterotrimeric G-Proteins mediated Phototransduction Cascade in retinal rod discs of the eyes. This cascade is also known as the Visual Cycle or Visual Signal Transduction. Dietary Vitamin-A in the blood plasma is usually complexed with pRBPs (Plasma Retinol-Binding Proteins) and Ttr (Transthyretin) (Ref.3). This facilitates the transfer of insoluble Vitamin-A between tissues, principally from storage sites in the liver to peripheral tissues. After being diffused into the RPE (Retinal Pigment Epithelium) Vitamin-A binds to cRBPs (Cellular Retinol-Binding Proteins) and is esterified to form all-trans-Retinyl Esters by the catalytic activity of LRAT (Lecithin Retinol Acyltransferase). LRAT also acts as a molecular switch for the chaperone RPE65 (Retinal Pigment Epithelium-Specific Protein-65kDa) and interconvert mRPE65 (Membrane-Associated RPE65) to sRPE65 (Soluble RPE65) and vice versa. mRPE65 is triply palmitoylated and is a chaperone for all-trans-Retinyl Esters, allowing their entry into the Visual Cycle for processing into 11-cis-Retinal, where as, sRPE65 is not palmitoylated and is a chaperone for Vitamin-A. Thus, the palmitoylation of RPE65 controls its ligand binding selectivity. RPE65 along with RDHs (Retinol Dehydrogenases) are essential for the biosynthesis of 11-cis-Retinal, the Chromophore of Rhodopsin. In the RPE 11-cis-Retinal binds to CRALBP (Cellular Retinaldehyde-Binding Protein) and is then diffused into the cytosol (that is IPM (Interphotoreceptor Matrix)) where it binds to IRBP (Interstitial Retinol-Binding Protein) and is transported to retinal rod discs (Ref.4).

The signaling cascade responsible for sensing light in vertebrates is initiated by Rhodopsin in discs of rod cells. The eyes of vertebrates contain Photo pigments in stacked membranes (discs) inside of the Photoreceptor nerve cells. In the retina of higher vertebrates both rod cells (for vision at low light levels) and cone cells (responsible for colour view) are present. Rhodopsin is able to absorb light in the visible range (500nm in wavelength) only because it contains 11-cis-Retinal, a derivative of Vitamin-A, as a small molecule Chromophore and hence initiates the signaling cascade. Rhodopsin is formed when apoprotein, Opsin gets covalently linked to 11-cis-Retinal. When light is absorbed, 11-cis-Retinal isomerizes to all-trans-Retinal, changing the shape of the molecule and the receptor it is bound to. Then a series of conformation changes in Rhodopsin leads to the formation of photoexcited Metarhodopsin-II [Rhodopsin (500nm) --->Batho-Rhodopsin (543nm) --->Lumi-Rhodopsin (497nm) --->Meta-Rhodopsin-I (480nm) --->Meta-Rhodopsin-II (380nm)] (Ref.5). This change in Rhodopsin’s shape alters its interaction with Transducins, member of the G-Protein gene family that has specific role in Visual Signal Transduction. The intermediate Metarhodopsin-II is the signaling state capable of interacting with the G-Protein. Metarhodopsin-II activates the heteromeric G-protein Transducins. The GTP bound GN-AlphaT (Guanine Nucleotide-Binding Protein G(t)-Alpha) Subunits) is liberated and then binds to the inhibitory Gamma-subunit of PDE (Phosphodiesterase) and removes it. The PDE is now able to hydrolyze cGMP (Cyclic Guanosine Monophosphate) (Ref.4 & 6).

The hydrolysis of cGMP to GMP following illumination closes the cGMP-Gated channels through allosteric mechanism (that is when GMP binds to the channels) and stops the Ca2+ (Calcium) and Na+ (Sodium) ions inflow. In resting rod cells or in low radiation, high levels of cGMP and Ca2+ associate with a cGMP-Gated channels and the NCX (Na+/Ca2+ Exchanger) in the plasma membrane, keeping the channels open and the membrane of the resting rod cells depolarized. This elevates the intracellular Ca2+ ion levels. The hydrolysis of cGMP following illumination stops the Na+ and Ca2+ inflow (Ref.7 & 8). This leads to the hyper-polarization of these cells, which changes the transmission of Glutamate-mediated neuronal signals. The rod cell in the resting state releases high levels of the inhibitory neurotransmitter Glutamate, while the release of Glutamate is repressed by the hyper-polarization in the presence of light to trigger a downstream action potential by ganglion cells that convey signals to the brain. The Ca2+ which enters the cell activate GCAPs (Guanylyl Cyclase Activating Proteins), which in turn activate GC (Guanylate Cyclase) to rapidly produce more cGMP, ending the hyper-polarization and returning the cell to its resting depolarized state. Moreover GTP hydrolysis by GC terminates the PDE activation by GTP bound GN-AlphaT leading to the reconstitution of cGMP inside the cells. Elevation of cGMP level is partly mediated by RGS9 (Regulator of G-Protein Signaling-9) that down regulates GTP-GN-AlphaT function (Ref.9 & 10). cGMP activates PLC-Beta (Phospholipase-C-Beta) that cleaves PIP2 (Phosphatidylinositol-4,5-bisphosphate) to generate DAG (Diacylglycerol) and IP3 (Inositol-1,4,5-trisphosphate). IP3 modulates activation of RHOK (Rhodopsin Kinase), Rcv1 (Recoverin), CaBP (Calcium Binding Protein) and PPEF2 (Protein Phosphatase-EF-hand Calcium Binding Domain-2) with the release of Ca2+ through IP3R (IP3 Receptor). DAG further activates PKC (Protein Kinase-C). Ca2+ activated HpcaL (Hippocalcin-Like) induce phosphorylation of photoexcited Metarhodopsin-II through GRK4 (G Protein-Coupled Receptor Kinase-4). This phosphorylation is also enhanced by the action of RHOK, Rcv1, PPEF2 and PKC. Phosphorylation causes binding of visual Arrestin to Rhodopsin, and stops its ability to activate Transducins. This helps to terminate the receptor activation signal and subsequently the action of PDE that hydrolyze cGMP. This process inactivates the signaling cascade, returning Rhodopsin to its pre-activated state that is Opsin. The Schiff base structure connecting Opsin and all-trans-Retinal is deprotonated, resulting in the separation of both moieties. all-trans-Retinal is reconverted back to 11-cis-Retinal through the process of isomerization and again binds to Opsin. Dissociation and re-association of Retinal, dephosphorylation of Rhodopsin and release of Arrestin all return Rhodopsin to its ready state, prepared once again to respond to light. Illumination can now initiate another reaction cycle (Ref.11, 12 & 13).

Photoreceptors are thus designed for the extreme conditions of very low and high activities in dark and light, respectively. Mutations in the genes necessary for the metabolism of Vitamin-A and cycling of Retinoids between the Photoreceptors and RPE is as an important class of genetic defects responsible for Retinal Dystrophies and Dysfunctions. Both Vitamin-A excess and deficiency are known to cause birth defects. Vitamin-A deficiency among children is the leading preventable cause of Blindness (Ref.4). The earliest evidence of Vitamin-A deficiency is Impaired Dark Adaptation or Night Blindness. Mild Vitamin-A deficiency result in changes in the conjunctiva (corner of the eye) called Bitots Spots. Severe or prolonged Vitamin-A deficiency causes a condition called Xeropthalmia (Dry Eye), characterized by changes in the cells of the cornea (clear covering of the eye) that ultimately result in Corneal Ulcers, Scarring, and Blindness. Vitamin-A deficiency is also considered as a Nutritionally Acquired Immunodeficiency Disease. Vitamin-A is commonly known as the anti-infective Vitamin, because it is required for normal functioning of the immune system. Vitamin-A reduce Carcinogenesis significantly in skin, breast, liver, colon, prostate, and other sites. However, the relationship between the consumption of preformed Vitamin-A and Cancer in humans are less clear (Ref.14).