id: PW:0000962
rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000962
title: visual phototransduction pathway
description_xrefs:
- GO:0007602
- KEGG:map04774
description: 'Two types of photoreceptors in the vertebrate retina mediate the light response: the rods
  which mediate vision in dim light and the cones which mediate bright light and color vision. Both sense
  light with a visual pigment composed of vitamin A derived chromophore 11-cis retinal and a G-protein
  coupled receptor (GPCR) to which the chromophore is covalently bound. Humans have one rod and three
  cones for long, medium- and short-waves. Rods and cones differ in their morphology, details of signalingand
  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.'
diagram_image: https://rgd.mcw.edu/pathway/PW0000962/visual%20phototransduction%20pathway/pwmap.png
pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000962/visual%20phototransduction%20pathway/visual%20phototransduction%20pathway.gpp
diagram_pathway_links:
- id: PW:0001005
  label: retinoid cycle metabolic pathway
diagram_gene_links:
- id: RGD:621385
  label: Arr3
- id: RGD:621815
  label: Cnga1
- id: RGD:70948
  label: Cnga3
- id: RGD:621809
  label: Cngb1
- id: RGD:1565364
  label: Cngb3
- id: RGD:1304683
  label: Gnat1
- id: RGD:1309514
  label: Gnat2
- id: RGD:619712
  label: Grk1
- id: RGD:1347561
  label: GRK7
- id: RGD:1308712
  label: Guca1a
- id: RGD:1308191
  label: Guca1b
- id: RGD:620438
  label: Gucy2e
- id: RGD:620439
  label: Gucy2f
- id: RGD:620258
  label: Rcvrn
- id: RGD:3573
  label: Rho
- id: RGD:3619
  label: Sag
- id: RGD:620080
  label: Slc24a1
- id: RGD:628650
  label: Slc24a2
diagram_chemicals:
- id: CHEBI:15035
  label: 11-cis-retinal
- id: PUBCHEM.COMPOUND:6804
  label: 5'-GMP
- id: CHEBI:22984
  label: ca efflux
- id: CHEBI:16356
  label: cGMP
- id: PUBCHEM.COMPOUND:33032
  label: glutamate
- id: CHEBI:15996
  label: GTP
diagram_edges:
- source: 11-cis-retinal
  relation: associated_with
  target: Rho
- source: 11-cis-retinal
  relation: associated_with
  target: cone opsins
- source: Arr3
  relation: associated_with
  target: cone opsins
- source: Ca-in
  relation: negatively_affects
  target: Guca1a
- source: Ca-in
  relation: negatively_affects
  target: Guca1b
- source: Cnga1
  relation: positively_affects
  target: Ca-in
- source: Cnga3
  relation: positively_affects
  target: Ca-in
- source: Cngb1
  relation: positively_affects
  target: Ca-in
- source: Cngb3
  relation: positively_affects
  target: Ca-in
- source: GRK7
  relation: negatively_affects
  target: cone opsins
- source: GTP
  relation: positively_affects
  target: cGMP_restored
- source: Grk1
  relation: negatively_affects
  target: Rho
- source: Guca1a
  relation: associated_with
  target: Gucy2e
- source: Guca1b
  relation: associated_with
  target: Gucy2f
- source: Rcvrn
  relation: negatively_affects
  target: Grk1
- source: Rgs9 complex
  relation: negatively_affects
  target: Gnat1
- source: Rho
  relation: associated_with
  target: Sag
- source: Rho
  relation: associated_with
  target: transducin complex
- source: cGMP
  relation: positively_affects
  target: 5'-GMP
- source: cGMP_restored
  relation: associated_with
  target: Cnga1
- source: cGMP_restored
  relation: associated_with
  target: Cnga3
- source: cGMP_restored
  relation: associated_with
  target: Cngb1
- source: cGMP_restored
  relation: associated_with
  target: Cngb3
- source: ca efflux
  relation: negatively_affects
  target: Rcvrn
- source: ca efflux
  relation: positively_affects
  target: Ca-out
- source: cone opsins
  relation: associated_with
  target: transducin complex
- source: glutamate
  relation: negatively_affects
  target: OFF-cone bipolar cell
- source: membrane hyperpolarization
  relation: negatively_affects
  target: glutamate
diagram_labels:
- ca efflux --+> Guca1a
- ca efflux --+> Guca1b
- Ca-in --+> Rcvrn
- central nervous system
- cone opsins --+> Gnat2
- glutamate --+> ON-cone bipolar cell
- glutamate --+> rod bipolar cell
- Gnat1 --+> Pde6 complex
- Gnat2 --+> Pde6 complex
- Guca1a --+> Gucy2e
- Guca1b --+> Gucy2f
- light
- light --+> 11-cis-retinal
- membrane hyperpolarization
- OFF-cone bipolar cell
- ON-cone bipolar cell
- Rho --+> Gnat1
- rod bipolar cell
- visual perception processing
diagram_other_links:
- href: /wg/home/pathway2/molecular-pathways2/cone-opsins
  label: cone opsins
- href: /wg/home/pathway2/molecular-pathways2/pde6-complex
  label: Pde6 complex
- href: /wg/home/pathway2/molecular-pathways2/rgs9-complex
  label: Rgs9 complex
- href: /wg/home/pathway2/molecular-pathways2/transducin-complex
  label: transducin complex
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