Suzanne de Bruijn

17 General introduction TheRPE layer surrounds the tips of theouter segments of thephotoreceptors ( Figure1B ). It has a key role in maintaining the structural integrity and normal function of the retina and is involved in a variety of functions: (1) it supports and nourishes the photoreceptor cells, and is firmly attached to the vascular layer (the choroid), (2) it contributes to the blood-retina barrier and controls the exchange of nutrients, growth factors and waste products, (3) it absorbs the excess of light that is projected on the retina, (4) it contributes to the regeneration of photopigment molecules after light absorption and (5) it plays a role in the phagocytosis of the outer membrane discs of the photoreceptors. The outer segments have a limited life span of ~12 days and are continuously renewed at their base. The oldest discs are shed from the tip and the RPE has a critical role in removing the expended discs. 10 Phototransduction Phototransduction is the biochemical process that is initiated after a photon is absorbed by the photopigment molecules in the photoreceptor cells. These photopigments contain a light-absorbing chromophore, retinal (a vitamin Aderivative), which is coupled to an opsin protein. The different types of photoreceptor cells (rod, S-, M- and L-cones) differ in the type of opsin molecules. When retinal (i.e. 11-cis-retinal) absorbs a photon, it is converted to all-trans-retinal. The coupled opsin protein subsequently induces the activation of the intracellular messenger molecule transducin. The activation of transducin will trigger a signaling cascade, ultimately leading to the hydrolysis of cyclic guanosine monophosphate (cGMP). As a result, the cGMP concentration in the outer segments will be lowered, and the cGMP-gated cation channels in the outer segments will close. The subsequent reduction of inflow of cations will cause hyperpolarization of the cell membrane. This light-dependent change in photoreceptor membrane potential leads to lower neurotransmitter release at the cell’s synaptic terminal. 7 At dim light conditions, cGMP is not hydrolyzed and therefore the amount of open calcium channels is relatively high. Because of the high influx of cations (Na + and Ca 2+ ) in the outer segment discs, the photoreceptor cell is depolarized and neurotransmitter release is increased. The signaling cascade is stopped when activated photopigment is rapidly phosphorylated by the responsible kinase, which leads to binding of the protein arrestin to the photopigment. This will block the ability of the photopigment to activate transducin. In this final stage of the retinoid acid cycle, restoration of the retinal molecule to its original configuration, 11-cis-retinal, takes place. All-trans-retinal dissociates from opsin and diffuses in the cytosol of the outer segment and is converted into all-