Visual phototransduction

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Visual phototransduction is the sensory transduction process of the visual system by which light is detected by photoreceptor cells (rods and cones) in the vertebrate retina. A photon is absorbed by a retinal chromophore (each bound to an opsin), which initiates a signal cascade through several intermediate cells, then through the retinal ganglion cells (RGCs) comprising the optic nerve.

Contents

Overview

Light enters the eye, passes through the optical media, then the inner neural layers of the retina before finally reaching the photoreceptor cells in the outer layer of the retina. The light may be absorbed by a chromophore bound to an opsin, which photoisomerizes the chromophore, initiating both the visual cycle, which "resets" the chromophore, and the phototransduction cascade, which transmits the visual signal to the brain. The cascade begins with graded polarisation (an analog signal) of the excited photoreceptor cell, as its membrane potential increases from a resting potential of -70 mV, proportional to the light intensity. At rest, the photoreceptor cells are continually releasing glutamate at the synaptic terminal to maintain the potential. [1] The transmitter release rate is lowered (hyperpolarization) as light intensity increases. Each synaptic terminal makes up to 500 contacts with horizontal cells and bipolar cells. [1] These intermediate cells (along with amacrine cells) perform comparisons of photoreceptor signals within a receptive field, but their precise functionalities are not well understood. The signal remains as a graded polarization in all cells until it reaches the RGCs, where it is converted to an action potential and transmitted to the brain. [1]

Photoreceptors

The photoreceptor cells involved in vertebrate vision are the rods, the cones, and the photosensitive ganglion cells (ipRGCs). These cells contain a chromophore (11-cis-retinal, the aldehyde of vitamin A1 and light-absorbing portion) that is bound to a cell membrane protein, opsin. Rods are responsible for vision under low light intensity and contrast detections. Because they all have the same response across frequencies, no color information can be deduced from the rods only, as in low light conditions for example. Cones, on the other hand, are of different kinds with different frequency response, such that color can be perceived through comparison of the outputs of different kinds of cones. Each cone type responds best to certain wavelengths, or colors, of light because each type has a slightly different opsin. The three types of cones are L-cones, M-cones and S-cones that respond optimally to long wavelengths (reddish color), medium wavelengths (greenish color), and short wavelengths (bluish color) respectively. Humans have trichromatic photopic vision consisting of three opponent process channels that enable color vision. [2] Rod photoreceptors are the most common cell type in the retina and develop quite late. Most cells become postmitotic before birth, but differentiation occurs after birth. In the first week after birth, cells mature and the eye becomes fully functional at the time of opening. The visual pigment rhodopsin (rho) is the first known sign of differentiation in rods. [3]

Transduction process

To understand the photoreceptor's behavior to light intensities, it is necessary to understand the roles of different currents.

There is an ongoing outward potassium current through nongated K+-selective channels. This outward current tends to hyperpolarize the photoreceptor at around −70 mV (the equilibrium potential for K+).

There is also an inward sodium current carried by cGMP-gated sodium channels. This "dark current" depolarizes the cell to around −40 mV. This is significantly more depolarized than most other neurons.

A high density of Na+-K+ pumps enables the photoreceptor to maintain a steady intracellular concentration of Na+ and K+.

When light intensity increases, the potential of the membrane decreases (hyperpolarization). Because as the intensity increases, the release of the stimulating neurotransmitter glutamate of the photoreceptors is reduced. When light intensity decreases, that is, in the dark environment, glutamate release by photoreceptors increases. This increases the membrane potential and produces membrane depolarization. [1]

In the dark

Photoreceptor cells are unusual cells in that they depolarize in response to absence of stimuli or scotopic conditions (darkness). In photopic conditions (light), photoreceptors hyperpolarize to a potential of −60 mV.

In the dark, cGMP levels are high and keep cGMP-gated sodium channels open allowing a steady inward current, called the dark current. This dark current keeps the cell depolarized at about −40 mV, leading to glutamate release which inhibits excitation of neurons.

The depolarization of the cell membrane in scotopic conditions opens voltage-gated calcium channels. An increased intracellular concentration of Ca2+ causes vesicles containing glutamate, a neurotransmitter, to merge with the cell membrane, therefore releasing glutamate into the synaptic cleft, an area between the end of one cell and the beginning of another neuron. Glutamate, though usually excitatory, functions here as an inhibitory neurotransmitter.

In the cone pathway, glutamate:

In the light

In summary: Light closes cGMP-gated sodium channels, reducing the influx of both Na+ and Ca2+ ions. Stopping the influx of Na+ ions effectively switches off the dark current. Reducing this dark current causes the photoreceptor to hyperpolarise, which reduces glutamate release which thus reduces the inhibition of retinal nerves, leading to excitation of these nerves. This reduced Ca2+ influx during phototransduction enables deactivation and recovery from phototransduction, as discussed below in § Deactivation of the phototransduction cascade.

Representation of molecular steps in photoactivation (modified from Leskov et al., 2000 ). Depicted is an outer membrane disk in a rod. Step 1: Incident photon (hn) is absorbed and activates a rhodopsin (likewise photopsin) by conformational change in the disk membrane to R*. Step 2: Next, R* makes repeated contacts with transducin molecules, catalyzing its activation to G* by the release of bound GDP in exchange for cytoplasmic GTP, which expels its b and g subunits. Step 3: G* binds inhibitory g subunits of the phosphodiesterase (PDE) activating its a and b subunits. Step 4: Activated PDE hydrolyzes cGMP. Step 5: Guanylyl cyclase (GC) synthesizes cGMP, the second messenger in the phototransduction cascade. Reduced levels of cytosolic cGMP cause cyclic nucleotide gated channels to close preventing further influx of Na and Ca . Phototransduction.png
Representation of molecular steps in photoactivation (modified from Leskov et al., 2000 ). Depicted is an outer membrane disk in a rod. Step 1: Incident photon (hν) is absorbed and activates a rhodopsin (likewise photopsin) by conformational change in the disk membrane to R*. Step 2: Next, R* makes repeated contacts with transducin molecules, catalyzing its activation to G* by the release of bound GDP in exchange for cytoplasmic GTP, which expels its β and γ subunits. Step 3: G* binds inhibitory γ subunits of the phosphodiesterase (PDE) activating its α and β subunits. Step 4: Activated PDE hydrolyzes cGMP. Step 5: Guanylyl cyclase (GC) synthesizes cGMP, the second messenger in the phototransduction cascade. Reduced levels of cytosolic cGMP cause cyclic nucleotide gated channels to close preventing further influx of Na and Ca .
  1. A photon interacts with a retinal molecule in an opsin complex in a photoreceptor cell. The retinal undergoes isomerisation, changing from the 11-cis-retinal to the all-trans-retinal configuration.
  2. Opsin therefore undergoes a conformational change to metarhodopsin II.
  3. Metarhodopsin II activates a G protein known as transducin. This causes transducin to dissociate from its bound GDP, and bind GTP; then the alpha subunit of transducin dissociates from the beta and gamma subunits, with the GTP still bound to the alpha subunit.
  4. The alpha subunit-GTP complex activates phosphodiesterase, also known as PDE6. It binds to one of two regulatory subunits of PDE (which itself is a tetramer) and stimulates its activity.
  5. PDE hydrolyzes cGMP, forming GMP. This lowers the intracellular concentration of cGMP and therefore the sodium channels close. [5]
  6. Closure of the sodium channels causes hyperpolarization of the cell due to the ongoing efflux of potassium ions.
  7. Hyperpolarization of the cell causes voltage-gated calcium channels to close.
  8. As the calcium level in the photoreceptor cell drops, the amount of the neurotransmitter glutamate that is released by the cell also drops. This is because calcium is required for the glutamate-containing vesicles to fuse with cell membrane and release their contents (see SNARE proteins).
  9. A decrease in the amount of glutamate released by the photoreceptors causes depolarization of on-center bipolar cells (rod and cone On bipolar cells) and hyperpolarization of cone off-center bipolar cells.

Deactivation of the phototransduction cascade

In light, low cGMP levels close Na+ and Ca2+ channels, reducing intracellular Na+ and Ca2+. During recovery (dark adaptation), the low Ca2+ levels induce recovery (termination of the phototransduction cascade), as follows:

  1. Low intracellular Ca2+ causes Ca2+ to dissociate from guanylate cyclase activating protein (GCAP). The liberated GCAP ultimately restores depleted cGMP levels, which re-opens the cGMP-gated cation channels (restoring dark current).
  2. Low intracellular Ca2+ causes Ca2+ to dissociate from GTPase-activating protein (GAP), also known as regulator of G protein signaling. The liberated GAP deactivates transducin, terminating the phototransduction cascade (restoring dark current).
  3. Low intracellular Ca2+ makes intracellular Ca-recoverin-RK dissociate into Ca2+ and recoverin and rhodopsin kinase (RK). The liberated RK then phosphorylates the Metarhodopsin II, reducing its binding affinity for transducin. Arrestin then completely deactivates the phosphorylated-metarhodopsin II, terminating the phototransduction cascade (restoring dark current).
  4. Low intracellular Ca2+ make the Ca2+/calmodulin complex within the cGMP-gated cation channels more sensitive to low cGMP levels (thereby, keeping the cGMP-gated cation channel open even at low cGMP levels, restoring dark current) [6]

In more detail:

GTPase Accelerating Protein (GAP) of RGS (regulators of G protein signaling) interacts with the alpha subunit of transducin, and causes it to hydrolyse its bound GTP to GDP, and thus halts the action of phosphodiesterase, stopping the transformation of cGMP to GMP. This deactivation step of the phototransduction cascade (the deactivation of the G protein transducer) was found to be the rate limiting step in the deactivation of the phototransduction cascade. [7]

In other words: Guanylate Cyclase Activating Protein (GCAP) is a calcium binding protein, and as the calcium levels in the cell have decreased, GCAP dissociates from its bound calcium ions, and interacts with Guanylate Cyclase, activating it. Guanylate Cyclase then proceeds to transform GTP to cGMP, replenishing the cell's cGMP levels and thus reopening the sodium channels that were closed during phototransduction.

Finally, Metarhodopsin II is deactivated. Recoverin, another calcium binding protein, is normally bound to Rhodopsin Kinase when calcium is present. When the calcium levels fall during phototransduction, the calcium dissociates from recoverin, and rhodopsin kinase is released and phosphorylates metarhodopsin II, which decreases its affinity for transducin. Finally, arrestin, another protein, binds the phosphorylated metarhodopsin II, completely deactivating it. Thus, finally, phototransduction is deactivated, and the dark current and glutamate release is restored. It is this pathway, where Metarhodopsin II is phosphorylated and bound to arrestin and thus deactivated, which is thought to be responsible for the S2 component of dark adaptation. The S2 component represents a linear section of the dark adaptation function present at the beginning of dark adaptation for all bleaching intensities.

Visual cycle

The absorption of light leads to an isomeric change in the retinal molecule. 1415 Retinal Isomers.jpg
The absorption of light leads to an isomeric change in the retinal molecule.

The visual cycle occurs via G-protein coupled receptors called retinylidene proteins which consists of a visual opsin and a chromophore 11-cis-retinal. The 11-cis-retinal is covalently linked to the opsin receptor via Schiff base. When it absorbs a photon, 11-cis-retinal undergoes photoisomerization to all-trans-retinal, which changes the conformation of the opsin GPCR leading to signal transduction cascades which causes closure of cyclic GMP-gated cation channel, and hyperpolarization of the photoreceptor cell. Following photoisomerization, all-trans-retinal is released from the opsin protein and reduced to all-trans-retinol, which travels to the retinal pigment epithelium to be "recharged". It is first esterified by lecithin retinol acyltransferase (LRAT) and then converted to 11-cis-retinol by the isomerohydrolase RPE65. The isomerase activity of RPE65 has been shown; it is uncertain whether it also acts as the hydrolase. [8] Finally, it is oxidized to 11-cis-retinal before traveling back to the photoreceptor cell outer segment where it is again conjugated to an opsin to form new, functional visual pigment (retinylidene protein), namely photopsin or rhodopsin.

In invertebrates

Visual phototransduction in invertebrates like the fruit fly differs from that of vertebrates, described up to now. The primary basis of invertebrate phototransduction is the PI(4,5)P2 cycle. Here, light induces the conformational change into rhodopsin and converts it into meta-rhodopsin. This helps in dissociation of G-protein complex. Alpha sub-unit of this complex activates the PLC enzyme (PLC-beta) which hydrolyze the PIP2 into DAG. This hydrolysis leads to opening of TRP channels and influx of calcium.[ citation needed ]

Invertebrate photoreceptor cells differ morphologically and physiologically from their vertebrate counterparts. Visual stimulation in vertebrates causes a hyperpolarization (weakening) of the photoreceptor membrane potential, whereas invertebrates experience a depolarization with light intensity. Single-photon events produced under identical conditions in invertebrates differ from vertebrates in time course and size. Likewise, multi-photon events are longer than single-photon responses in invertebrates. However, in vertebrates, the multi-photon response is similar to the single-photon response. Both phyla have light adaptation and single-photon events are smaller and faster. Calcium plays an important role in this adaptation. Light adaptation in vertebrates is primarily attributable to calcium feedback, but in invertebrates cyclic AMP is another control on dark adaptation. [9] [ verification needed ]

Related Research Articles

<span class="mw-page-title-main">Rhodopsin</span> Light-sensitive receptor protein

Rhodopsin, also known as visual purple, is a protein encoded by the RHO gene and a G-protein-coupled receptor (GPCR). It is the opsin of the rod cells in the retina and a light-sensitive receptor protein that triggers visual phototransduction in rods. Rhodopsin mediates dim light vision and thus is extremely sensitive to light. When rhodopsin is exposed to light, it immediately photobleaches. In humans, it is regenerated fully in about 30 minutes, after which the rods are more sensitive. Defects in the rhodopsin gene cause eye diseases such as retinitis pigmentosa and congenital stationary night blindness.

<span class="mw-page-title-main">Photoreceptor cell</span> Type of neuroepithelial cell

A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light into signals that can stimulate biological processes. To be more specific, photoreceptor proteins in the cell absorb photons, triggering a change in the cell's membrane potential.

<span class="mw-page-title-main">Transducin</span>

Transducin (Gt) is a protein naturally expressed in vertebrate retina rods and cones and it is very important in vertebrate phototransduction. It is a type of heterotrimeric G-protein with different α subunits in rod and cone photoreceptors.

<span class="mw-page-title-main">Rod cell</span> Photoreceptor cells that can function in lower light better than cone cells

Rod cells are photoreceptor cells in the retina of the eye that can function in lower light better than the other type of visual photoreceptor, cone cells. Rods are usually found concentrated at the outer edges of the retina and are used in peripheral vision. On average, there are approximately 92 million rod cells in the human retina. Rod cells are more sensitive than cone cells and are almost entirely responsible for night vision. However, rods have little role in color vision, which is the main reason why colors are much less apparent in dim light.

In visual physiology, adaptation is the ability of the retina of the eye to adjust to various levels of light. Natural night vision, or scotopic vision, is the ability to see under low-light conditions. In humans, rod cells are exclusively responsible for night vision as cone cells are only able to function at higher illumination levels. Night vision is of lower quality than day vision because it is limited in resolution and colors cannot be discerned; only shades of gray are seen. In order for humans to transition from day to night vision they must undergo a dark adaptation period of up to two hours in which each eye adjusts from a high to a low luminescence "setting", increasing sensitivity hugely, by many orders of magnitude. This adaptation period is different between rod and cone cells and results from the regeneration of photopigments to increase retinal sensitivity. Light adaptation, in contrast, works very quickly, within seconds.

<span class="mw-page-title-main">Guanylate cyclase</span> Lyase enzyme that synthesizes cGMP from GTP

Guanylate cyclase is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) and pyrophosphate:

<span class="mw-page-title-main">Retinal</span> Chemical compound

Retinal is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision).

<span class="mw-page-title-main">Retina bipolar cell</span> Type of neuron

As a part of the retina, bipolar cells exist between photoreceptors and ganglion cells. They act, directly or indirectly, to transmit signals from the photoreceptors to the ganglion cells.

<span class="mw-page-title-main">Melanopsin</span> Mammalian protein found in Homo sapiens

Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4. In the mammalian retina, there are two additional categories of opsins, both involved in the formation of visual images: rhodopsin and photopsin in the rod and cone photoreceptor cells, respectively.

Photopigments are unstable pigments that undergo a chemical change when they absorb light. The term is generally applied to the non-protein chromophore moiety of photosensitive chromoproteins, such as the pigments involved in photosynthesis and photoreception. In medical terminology, "photopigment" commonly refers to the photoreceptor proteins of the retina.

<span class="mw-page-title-main">Cyclic nucleotide–gated ion channel</span> Family of transport proteins

Cyclic nucleotide–gated ion channels or CNG channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various tissue and cell types, and are significant in sensory transduction as well as cellular development. Their function can be the result of a combination of the binding of cyclic nucleotides and either a depolarization or a hyperpolarization event. Initially discovered in the cells that make up the retina of the eye, CNG channels have been found in many different cell types across both the animal and the plant kingdoms. CNG channels have a very complex structure with various subunits and domains that play a critical role in their function. CNG channels are significant in the function of various sensory pathways including vision and olfaction, as well as in other key cellular functions such as hormone release and chemotaxis. CNG channels have also been found to exist in prokaryotes, including many spirochaeta, though their precise role in bacterial physiology remains unknown.

<span class="mw-page-title-main">Opsin</span> Class of light-sensitive proteins

Animal opsins are G-protein-coupled receptors and a group of proteins made light-sensitive via a chromophore, typically retinal. When bound to retinal, opsins become retinylidene proteins, but are usually still called opsins regardless. Most prominently, they are found in photoreceptor cells of the retina. Five classical groups of opsins are involved in vision, mediating the conversion of a photon of light into an electrochemical signal, the first step in the visual transduction cascade. Another opsin found in the mammalian retina, melanopsin, is involved in circadian rhythms and pupillary reflex but not in vision. Humans have in total nine opsins. Beside vision and light perception, opsins may also sense temperature, sound, or chemicals.

<span class="mw-page-title-main">Retina horizontal cell</span>

Horizontal cells are the laterally interconnecting neurons having cell bodies in the inner nuclear layer of the retina of vertebrate eyes. They help integrate and regulate the input from multiple photoreceptor cells. Among their functions, horizontal cells are believed to be responsible for increasing contrast via lateral inhibition and adapting both to bright and dim light conditions. Horizontal cells provide inhibitory feedback to rod and cone photoreceptors. They are thought to be important for the antagonistic center-surround property of the receptive fields of many types of retinal ganglion cells.

<span class="mw-page-title-main">Congenital stationary night blindness</span> Medical condition

Congenital stationary night blindness (CSNB) is a rare non-progressive retinal disorder. People with CSNB often have difficulty adapting to low light situations due to impaired photoreceptor transmission. These patients may also have reduced visual acuity, myopia, nystagmus, and strabismus. CSNB has two forms -- complete, also known as type-1 (CSNB1), and incomplete, also known as type-2 (CSNB2), which are distinguished by the involvement of different retinal pathways. In CSNB1, downstream neurons called bipolar cells are unable to detect neurotransmission from photoreceptor cells. CSNB1 can be caused by mutations in various genes involved in neurotransmitter detection, including NYX. In CSNB2, the photoreceptors themselves have impaired neurotransmission function; this is caused primarily by mutations in the gene CACNA1F, which encodes a voltage-gated calcium channel important for neurotransmitter release. CSNB has been identified in horses and dogs as the result of mutations in TRPM1, GRM6, and LRIT3 .

Rhodopsin kinase is a serine/threonine-specific protein kinase involved in phototransduction. This enzyme catalyses the following chemical reaction:

Retinylidene proteins, or rhodopsins in a broad sense, are proteins that use retinal as a chromophore for light reception. They are the molecular basis for a variety of light-sensing systems from phototaxis in flagellates to eyesight in animals. Retinylidene proteins include all forms of opsin and rhodopsin. While rhodopsin in the narrow sense refers to a dim-light visual pigment found in vertebrates, usually on rod cells, rhodopsin in the broad sense refers to any molecule consisting of an opsin and a retinal chromophore in the ground state. When activated by light, the chromophore is isomerized, at which point the molecule as a whole is no longer rhodopsin, but a related molecule such as metarhodopsin. However, it remains a retinylidene protein. The chromophore then separates from the opsin, at which point the bare opsin is a retinylidene protein. Thus, the molecule remains a retinylidene protein throughout the phototransduction cycle.

The visual cycle is a process in the retina that replenishes the molecule retinal for its use in vision. Retinal is the chromophore of most visual opsins, meaning it captures the photons to begin the phototransduction cascade. When the photon is absorbed, the 11-cis retinal photoisomerizes into all-trans retinal as it is ejected from the opsin protein. Each molecule of retinal must travel from the photoreceptor cell to the RPE and back in order to be refreshed and combined with another opsin. This closed enzymatic pathway of 11-cis retinal is sometimes called Wald's visual cycle after George Wald (1906–1997), who received the Nobel Prize in 1967 for his work towards its discovery.

<span class="mw-page-title-main">Retinal degeneration (rhodopsin mutation)</span> Retinopathy

Retinal degeneration is a retinopathy which consists in the deterioration of the retina caused by the progressive death of its cells. There are several reasons for retinal degeneration, including artery or vein occlusion, diabetic retinopathy, R.L.F./R.O.P., or disease. These may present in many different ways such as impaired vision, night blindness, retinal detachment, light sensitivity, tunnel vision, and loss of peripheral vision to total loss of vision. Of the retinal degenerative diseases retinitis pigmentosa (RP) is a very important example.

<span class="mw-page-title-main">William A. Hagins</span>

William Archer Hagins was an American medical researcher. He was chief of the Section of Membrane Biophysics in National Institute of Diabetes and Digestive and Kidney Diseases's Laboratory of Chemical Physics upon his retirement in 2007. Hagins and colleagues made the seminal discovery of the dark current in photoreceptor cells. This finding became central to understanding how the visual cells worked and led to knowledge of the importance of reattaching a detached retina as soon as possible for continued use. As a fellow of Fulbright Program, he'd also served in the United States Navy as a Research Medical Officer. He joined NIDDK's Laboratory of Physical Biology in 1958, doing independent research in the Section of Photobiology, headed by Frederick Sumner Brackett. Hagins was a mentor to many, particularly through his work with the Brackett Foundation.

<span class="mw-page-title-main">Vertebrate visual opsin</span>

Vertebrate visual opsins are a subclass of ciliary opsins and mediate vision in vertebrates. They include the opsins in human rod and cone cells. They are often abbreviated to opsin, as they were the first opsins discovered and are still the most widely studied opsins.

References

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