and specific steps of chromophore regeneration. Overall, rods are very sensitive to light and respond to a single photon, the cones are less so. The mechanism of phototransduction on rod cells has been extensively studied; rhodopsin, the rod GPCR is considered a paradigm for the superfamily of 7 trans-membrane (7TM) GPCRs and the rhodopsin-like or A family/class in particular. Briefly, 11-cis retinal is buried in the core of the 7 TM; a lysine residue is the site for a protonated Schiff base linkage between receptor and ligand, further stabilized by nearby residues. In the absence of light 11-cis retinal acts as an inverse agonist by constraining the receptor in an inactive conformation. Upon light stimulation, the chromophore is isomerized to all-trans retinal, the Schiff base is deprotonated, a series of conformational changes in the photoreceptor follow and the isomerized choromophore is released. Rearrangement of TM5-TM6 opens up the binding site for the specific G protein transducin at the cytoplasmic site of the receptor. In the resting state, G proteins are heterotrimers consisting of alpha-GDP-bound, beta and gamma subunits; the alpha GTPase domain is conserved in all members of the G protein superfamily, including the small monomeric G proteins. The C-terminus of the alpha subunit is relatively flexible prior to binding, but adopts a helical structure subsequently; the conformational changes reverberate to the nucleotide binding site leading to release of GDP. Binding of GTP prompts dissociation of the GTP-alpha subunit from the receptor and the beta/gamma subunits. GTP-alpha interacts with and activate its target, the cyclic GMP phosphodiesterase (PDE). Active PDE hydrolyzes cGMP; the decrease in cGMP availability leads to closure of cGMP-gated cation channels resulting in membrane depolarization, decreased release of glutamate neurotransmitter and signaling to adjacent neurons. cGMP hydrolysis will continue for as long as G-alpha is GTP-bound. GTP hydrolysis occurs via the intrinsic GTPase activity of alpha transducin, further facilitated by the Rgs9 complex with GTPase-activating-protein activity (GAP). The signal, which is terminated via G protein inactivation, is also modulated at the level of the receptors. Specific kinases Grk1 and GRK7 (blue denotes human protein) phosphorylate the active photoreceptors which are then recognized by specific arrestin proteins and the interaction precludes binding of transducin to the active receptors. Light prompted closure of cation channels prevents calcium influx into the cell but not its efflux via the Na+/Ca2+, K+ exchanger of the Slc24 gene family. The overall decrease in intracellular calcium concentration provides several negative feedback loops resulting in restoration of cGMP levels and adjustment of photoreceptors light sensitivity usually referred to as 'light adaptation'. The guanylate cyclases, whose activity results in cGMP production, are constitutively bound to activator proteins (GCAPs), calcium binding proteins that inhibit the cyclases in the presence of calcium but stimulate them in its absence. Recoverin is another calcium binding protein; it inhibits Grk1 kinase activity in the presence of calcium and this effect is removed when calcium concentration decreases. Rods and cone cells synapse on bipolar (and horizontal) cells, in turn synapsing on amacrine and ganglion cells; the signal is relayed to the midbrain, the thalamus and the visual cortex where processing of visual perception and the aspects of visual experience take place. The cGMP-gated channel - a tetrameric complex belonging to the small family of cyclic-nucleotide-gated (CNG) cation channels is a non-selective cation channel; it does not get desensitized by ligands and maintains a steady inward current in darkness (dark current). In the absence of light the cells are sufficiently depolarized to allow for a sustained synaptic release of glutamate neurotransmitter which hyperpolarizes (inhibits) the ON-cone and rod and depolarizes (activates) the OFF-cone downstream bipolar cells. Glutamate, an excitatory neurotransmitter has an inhibitory effect on the ON-cone and rod bipolar cells; they express the metabotropic receptor Grm6, known as mGluR6, which is negatively coupled to a cation channel. Hyperpolarization of photoreceptor cells in response to light leads to decreased release of glutamate, reversing the hyperpolarizing 'sign' of light signal into a depolarizing one on these cells (decrease in glutamate and associated lack of activation of a specific G protein downstream of Grm6, further inactivated by its own GTPase activity in turn aided by a specific Rgs GAP complex, prompts the opening of the cation channel, possibly a member of the transient receptor potential [TRP] channels family). The sign is maintained at the OFF-cone cells which express the lower affinity ionotropic AMPA/kainite glutamate receptors and the cells are hyperpolarized. Thus, the separation of signals related to light increments (ON) and decrements (OFF) takes place at the first synapse of the retina. To sustain vision, all-trans retinal, resulting from the isomerization of the chromophore, needs to be converted back to the 11-cis isomer. This is accomplished through a series of reactions catalyzed by membrane-bound enzymes; the metabolic pathway is known as the retinoid or visual cycle. Visual phototransduction is a complex signaling pathway, continuously balancing the response to light and the modulation of that response. Mutations in a number of components in the visual phototransduction and retinoid cycle pathways have been linked to several human retinal degeneration and autosomal recessive diseases. To see the ontology report for annotations, Gviewer and download, click here ; to access a list of selected structures, click here . [Click to see associated GO term - GO:0007602 and KEGG map map04774]...(less)