Functional parts of the rods (rods) and cones (cones)^[1]

A photoreceptor, or photoreceptor cell, is a specialized type of neuron found in the eye's retina that is capable of phototransduction. The great biological importance of photoreceptors is that as cells they convert light (electromagnetic radiation) into the beginning of a chain of biological processes - these processes end elsewhere resulting in sight. More specifically, the photoreceptor absorbs photons from the visual field, and through a specific and complex biochemical pathway, signals this information through a change in its membrane potential. Ultimately, this information will be used by the visual system to form a complete representation of the visual world. Described here is a vertebrate photoreceptor. Invertebrate photoreceptor in organisms such as insects and molluscs are different in both their morphological organization and their underlying biochemical pathways.

For hundreds of years, in vertebrates photoreceptors were thought to come in only two main classes, though in some species a novel photoreceptor has recently been identified. The classic photoreceptors are rods and cones, with major functional differences between the two. The novel photoreceptor is a photorecpetive class of ganglion cells. Cones are adapted to detect colors, and function well in bright light; rods are more sensitive, but do not detect color well, being adapted for low light. In humans there are three different types of cone - responding respectively to short (blue), medium (green) and long (yellow-red) light. The human retina contains about 120 million rod cells and 6 million cone cells. The number and ratio of rods to cones varies among animals, dependent on whether the animal is primarily diurnal or nocturnal. Certain owls have a tremendous number of rods in their retinas — the eyes of the tawny owl are approximately 100 times more sensitive at night than those of humans.^[2].

Unlike rods and cones (classic photoreceptors) in terms of the history of science the novel photoreceptor has only been very recently discovered. This is a particularly fascinating area of active biological research as the key fundamental discoveries pertaining to it represent thus far the only radically fundamental discoveries in mammalian and human biology to be made in the early 21st century - and they continue to be made. For these reasons, and as it is anatomically and functionally quite distinct in many ways to rods and cones which share many similarities with each other, it is discussed in a separate chapter below, though it should be noted a visual role in common with classic photoreceptors for the photoreceptive ganglion cell has recently also been found.^[3]

Histology

Rod and cone photoreceptors have the same basic structure. Closest to the visual field (and farthest from the brain) is the axon terminal, which releases a neurotransmitter called glutamate to bipolar cells. Farther back is the Cell body, which contains the cell's organelles. Farther back still is the inner segment, a specialized part of the cell full of mitochondria. The chief function of the inner segment is to provide ATP (energy) for the sodium-potassium pump. Finally, closest to the brain (and farthest from the visual field) is the outer segment, the part of the photoreceptor that actually absorbs light. Outer segments are actually modified cilia that contain disks filled with opsin, the molecule that absorbs photons, as well as voltage-gated sodium channels.

The membranous photoreceptor protein opsin contains a pigment molecule called retinal. In rod cells, these together are called rhodopsin. In cone cells there are different types of opsins that combine with retinal to form pigments called photopsins. Three different classes of photopsins react to different ranges of light frequency, a differentation which eventually allows the nervous system to distinguish color. The function of the photoreceptor cell is to convert the light energy of the photon into a form of energy communicable to the nervous system and more readily usable to the organism: this conversion is called signal transduction.

In distinction ganglion cell photoreceptors are giant ganglion cells found in the inner retina with dendrites and long axons projecting to the pretectum (midbrain), suprachiasmatic nucleas (hypothalamus), and lateral geniculate (thalamus).

Humans

In humans, the visual system uses millions of photoreceptors to view, perceive, and analyze the visual world. With the exception of melanopsin-containing photosensitive ganglion cells, ocular photoreceptors are the only neurons in humans capable of phototransduction. All photoreceptors in humans are found either in the outer nuclear layer in the retina at the back of each eye, while the bipolar and ganglion cells that transmit information from photoreceptors to the brain are in front of them. This inverted arrangement significantly reduces acuity,^{citation needed} as light must travel through the axons and cell bodies of other neurons before reaching the photoreceptors. The retina contains two specializations to deal with this issue. First, a region at the center of the retina, called the fovea, containing only photoreceptors, is used for high visual acuity. Second, each retina contains a blind spot, an area where axons from the ganglion cells can go back through the retina to the brain.

Normalized typical human cone (and rod) absorbances (not responses) to different wavelengths of light^[4]

For hundreds of years humans were thought to have only two types of photoreceptors: rods and cones. Both transduce light into a change in membrane potential through the same signal transduction pathway (see below). However, they differ in the nature of the opsin they contain, and their function. Rods are used primarily to see at low levels of light, while cones are used to determine color, depth, and intensity. Furthermore, there are three types of cones, which differ in the spectrum of wavelengths of photons over which they absorb (see graph). Because cones respond to both the wavelength and intensity of light, a single cone cannot tell color; instead, color vision requires interactions of more than one type of cone (see below), primarily by comparing responses across different cone types.

It is important to note that older textbooks will not contain yet the most exciting discovery in the field of human photoreception and vision. In 2007 a novel ganglion cell photoreceptor class was isolated in rodless coneless humans, where it was found to mediate circadian rythms, behaviour, pupil reactions, and most exciting of all a component to unconscious and conscious sight.^[5] These non-rod non-cone photoreceptors in general are discussed later below.

Phototransduction

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Phototransduction is the complex process whereby the energy of a photon is used to change the inherent membrane potential of the photoreceptor -- and thereby signal to the nervous system that light is in the visual field.

Dark current

Unstimulated (in the dark), the voltage-gated sodium channels in the outer segment are open because cyclic GMP (cGMP) is bound to them. Hence, positively charged sodium ions enter the photoreceptor, depolarizing it to about -40 mV (resting potential in other nerve cells is usually -65 mV). This depolarizing current is often known as dark current.

Signal transduction pathway

The signal transduction pathway is the mechanism by which the energy of a photon signals a mechanism in the cell that leads to its electrical polarization. This polarization ultimately leads to either the transmittance or inhibition of a neural signal that will be fed to the brain via the optic nerve. The steps, or signal transduction pathway, in the vertebrate eye's rod and cone photoreceptors are then:

1. The rhodopsin or iodopsin in the outer segment absorbs a photon, changing the configuration of a retinal Schiff base cofactor inside the protein from the cis-form to the trans-form, causing the retinal to change shape.
2. This results in a series of unstable intermediates, the last of which binds stronger to the G protein in the membrane and activates transducin, a protein inside the cell. This is the first amplification step - each photoactivated rhodopsin triggers activation of about 100 transducins. (The shape change in the opsin activates a G protein called transducin.)
3. Each transducin then activates the enzyme cGMP-specific phosphodiesterase (PDE). (Transducin, in turn, activates the enzyme phosphodiesterase.)
4. PDE then catalyzes the hydrolysis of cGMP. This is the second amplification step, where a single PDE hydrolyses about 1000 cGMP molecules. (The enzyme hydrolyzes the second messenger cGMP to GMP)
5. With the intracellular concentration of cGMP reduced, the net result is closing of cyclic nucleotide-gated ion channels in the photoreceptor membrane because cGMP was keeping the channels open. (Because cGMP acts to keep Na⁺ ion channels open, the conversion of cGMP to GMP closes the channels.)
6. As a result, sodium ions can no longer enter the cell, and the photoreceptor hyperpolarizes (its charge inside the membrane becomes more negative). (The closing of Na⁺ channels hyperpolarizes the cell.)
7. This hyperpolarization means that less glutamate is released to the bipolar cell than before (see below). (The hyperpolarization of the cell slows the release of the neurotransmitter glutamate, which can either excite or inhibit the postsynaptic bipolar cells.)
8. Reduction in the release of glutamate means one population of bipolar cells will be depolarized and a separate population of bipolar cells will be hyperpolarized, depending on the nature of receptors (ionotropic or metabotropic) in the postsynaptic terminal (see receptive field).

Thus, a rod or cone photoreceptor actually releases less neurotransmitter when stimulated by light.

ATP provided by the inner segment powers the sodium-potassium pump. This pump is necessary to reset the initial state of the outer segment by taking the sodium ions that are entering the cell and pumping them back out.

Although photoreceptors are neurons, they do not conduct action potentials with the exception of the ganglion cell photoreceptor.

Advantages

Phototransduction in rods and cones is unique in that the stimulus (in this case, light) actually reduces the cell's response or firing rate, which is unusual for a sensory system where the stimulus usually increases the cell's response or firing rate. However, this system offers several key advantages.

First, the classic (rod or cone) photoreceptor is depolarized in the dark, which means many sodium ions are flowing into the cell. Thus, the random opening or closing of sodium channels will not affect the membrane potential of the cell; only the closing of a large amount of channels, through absorption of a photon, will affect it and signal that light is in the visual field. Hence, the system is noiseless.

Second, there is a lot of amplification in two stages of classic phototransduction: one pigment will activate many molecules of transducin, and one PDE will cleave many cGMPs. This amplification means that even the absorption of one photon will affect membrane potential and signal to the brain that light is in the visual field. This is the main feature which differentiates rod photoreceptors from cone photoreceptors. Rods are extremely sensitive and have the capacity of registering a single photon of light unlike cones. On the other hand, cones are known to have very fast kinetics in terms of rate of amplification of phototransduction unlike rods.

Function

Photoreceptors do not signal color; they only signal the presence of light in the visual field.

A given photoreceptor responds to both the wavelength and intensity of a light source. For example, red light at a certain intensity can produce the same exact response in a photoreceptor as green light of a different intensity. Therefore, the response of a single photoreceptor is ambiguous when it comes to color.

To determine color, the visual system compares responses across a population of photoreceptors (specifically, the three different cones with differing absorption spectra). To determine intensity, the visual system computes how many photoreceptors are responding. This is the mechanism that allows trichromatic color vision in humans and some other animals.

Signaling

The rod and cone photoreceptors signal their absorption of photons through a release of the neurotransmitter glutamate to bipolar cells at its axon terminal. Since the photoreceptor is depolarized in the dark, a high amount of glutamate is being released to bipolar cells in the dark. Absorption of a photon will hyperpolarize the photoreceptor and therefore result in the release of less glutamate at the presynaptic terminal to the bipolar cell.

Every rod or cone photoreceptor releases the same neurotransmitter, glutamate. However, the effect of glutamate differs in the bipolar cells, depending upon the type of receptor imbedded in that cell's membrane. When glutamate binds to an ionotropic receptor, the bipolar cell will depolarize (and therefore will hyperpolarize with light as less glutamate is released). On the other hand, binding of glutamate to a metabotropic receptor results in a hyperpolarization, so this bipolar cell will depolarize to light as less glutamate is released.

In essence, this property allows for one population of bipolar cells that gets excited by light and another population that gets inhibited by it, even though all photoreceptors show the same response to light. This complexity becomes both important and necessary for detecting color, contrast, edges, etc.

Further complexity arises from the various interconnections among bipolar cells, horizontal cells, and amacrine cells in the retina. The final result is differing populations of ganglion cells in the retina, a sub-population of which are also intrinsically photosensitive and use the photopigment melanopsin. Each conveys different information to the brain, for the final synthesis of a visual world.

Ganglion cell (non-rod non-cone) photoreceptors

In 1991 Russell G. Foster and colleagues including Ignacio Provencio discovered a non-rod non-cone photoreceptor in the eyes of mice where it was shown to mediate circadian rhythms i.e. the body's 24-hour biological clock. ^[6]. The fact that such a landmark discovery was published in a relatively obscure science journal shows the initial skepticism about the existence of non-rod non-cone photoreceptors within the scientific community, which continued to widely believe that the only photoreceptors were rods and cones as if this was written in stone - and why not, after all, as Foster himself notes, the eye had been the subject of detailed study for a continuous period of over 200 years, so at the time it seemed unlikely that great minds since Newton, Maxwell, through to Einstein and beyond, could have missed this receptor's existence, its functions, and its ramifications.^[7] But miss it they did and it fell to contemporary researchers to make the landmark discoveries in the field, ground-breaking discoveries that still continue to be made. These novel cells express the photopigment melanopsin which was first identified by Ignacio Provencio and colleagues who published in the Journal of Neuroscience in 2000.^[8] Note how after almost one whole decade major advances in the field would henceforth only be published in major biology and science journals, reflecting the gradual acceptance of the novel receptor by the scientific community. Robert Lucas and colleagues including Russell Foster were the first to show conclusively that cells containing the photopigment melanopsin absorb light maximally at different wavelength than those of rods and cones.^[9] Robert Lucas and colleagues including Foster also discovered that in mice the non-rod non-cone photoreceptor had a role in initiating the pupil light reflex and not only circadian / behavioural functions as previously thought, though the latter were also demonstrated by them using genetically engineered rodless coneless mice ^[10]. Samer Hattar and colleagues including David Berson in 2002 showed that in the rat intrinsically photosensitive retinal ganglion cells invariably expressed melanopsin and so melanopsin (and not rod or cone opsins) was most likely the visual pigment of phototransducing retinal ganglion cells that set the circadian clock and initiated other non-image-forming visual functions.^[11] This work is regarded by Current Biology, New Scientist and various other commentators as representing the discovery that the identity of the non-rod non-cone photoreceptor in mice was a class of retinal ganglion cells (RGCs).^[12] This was highly significant anatomically - ganglion cells reside in the inner retina, while classic photoreceptors (rods and cones) inhabit the outer retina, suggesting two parallel and anatomically distinct photoreceptor pathways. In the same year of 2005 Melyan and Qiu together with colleagues including Robert Lucas, Mark W Hankins and David Berson, showed that the melanopsin photopigment was the phototransduction pigment in ganglion cells.^[13][14]. Dennis Dacey with colleagues including Paul Gamlin showed in a species of Old World monkey that giant ganglion cells expressing melanopsin projected to the lateral geniculate nucleas.^[15] Previously only projections to the midbrain (pre-tectal nucleas) and hypothalamus (supra-chiasmatic nucleas) had been shown. However a visual role for the receptor was still unsuspected and unproven.

What about humans? Attempts started to be made to hunt down the receptor in humans. But humans posed special challenges and demanded a new model - for unlike in animals extensive ethical issues meant rod and cone loss could not be induced genetically or with chemicals so as to directly study the ganglion cells. So for many years only inferences could be drawn about the receptor in humans, though these were at times pertinent. In 2007 the breakthrough came when Farhan H. Zaidi and colleagues including Russell Foster, George Brainard, David Czeisler and Steven Lockley, after having teamed up with other workers on both sides of the Atlantic, published their pioneering work using rodless coneless humans. Current Biology subsequently announced in their 2008 editorial, commentary and despatches to scientists and ophthalmologists, that the non-rod non-cone photoreceptor had been conclusively discovered in humans using landmark experiments on rodless coneless humans by Zaidi and colleagues ^[16] The 2007 discovery of the novel receptor in humans, as well as the spectacular discovery made alongside that it mediated conscious sight, was trumpeted by Cell Press, New Scientist, and other science commentators in 2007.^[17], ^[18], ^[19] The workers found the identity of the non-rod non-cone photoreceptor in humans to be a ganglion cell in the inner retina as had been shown previously in rodless coneless models in some other mammals. The workers had tracked down patients with rare diseases wiping out classic rod and cone photoreceptor function but preserving ganglion cell function.^[20], ^[21], ^[22] Despite having no rods or cones the patients continued to exhibit circadian photoentrainment, circadian behavioural patterns, melanopsin suppression, and pupil reactions, with peak spectral sensitivities to environmental and experimental light matching that for the melanopsin photopigment. Their brains could also associate vision with light of this frequency. Jacob Schor comments that in addition to being an outstanding example of collaboration between different countries, as well as between clinicians and scientists, interest thenceforth started to be shown by clinicians including ophthalmologists with a view to understanding the new receptor's role in human diseases and as discussed below, blindness.^[23]

The use of rodless coneless humans allowed another possible role for the receptor to be studied. In 2007 arguably the most fascinating novel role was found for the photoreceptive ganglion cell. Farhan H. Zaidi and colleagues including Russell Foster, George Brainard, David Czeisler and Steven Lockley, showed that the retinal ganglion cell was a photoreceptor (at least in humans) for conscious sight and not only non-image-forming functions like circadian rhythms, behaviour and pupil reactions as previously thought.^[24] Humans were the perfect model in which to prove this function as they can describe sight readily to an observer which animals cannot do. Hence the receptor by its location anatomically in the inner retina as shown by these workers was the first cell to perceive light giving rise to vision. They also showed it responded most to blue light, suggesting it may have a role in mesopic vision and the old theory of a purely duplex retina with rod (dark) and cone (light) light vision was simplistic. Zaidi and colleagues' work with rodless coneless human subjects hence also opened the door into image-forming (visual) roles for the ganglion cell photoreceptor. It also made the important discovery that there are parallel pathways for vision - one classic rod and cone-based arising from the outer retina, the other a rudimentary visual brightness detector arising from the inner retina and which seems to be activated by light before the other.^[25] Classic photoreceptors also feed into the novel photoreceptor system, and colour constancy may be an important role as suggested by Foster. Like many of the key discoveries about the new receptor, the work by Zaidi and colleagues shatters hundreds of years of what science thought it knew about the most basic function of the eye and vision. The workers on the rodless coneless human model summarised their landmark paper noting for the first time that the receptor could be instrumental in understanding many diseases including major causes of blindness worldwide like glaucoma, a disease which affects ganglion cells, and the study of the receptor offered potential as a new avenue to explore in trying to find treatments for blindness. It is in these discoveries of the novel photoreceptor in humans and in the receptors role in vision, rather than its non-image-forming functions, where the receptor may have the greatest impact on society as a whole, though the impact of disturbed circadian rhythms is another area of relevance to clinical medicine.

Most work suggests that the peak spectral sensitivity of the receptor is between 460 and 481nm, though a minority of groups reported it being lower as far as 420nm. Steven Lockley et al in 2003 showed that 460 nm wavelengths of light suppress melatonin twice as much as longer 555 nm light. However, in more recent work by Farhan Zaidi, Steven Lockley and co-authors using rodless coneless human, it was found that what consciously led to light perception was a very intense 481nm stimuli - this means that the receptor in visual terms enables some rudimentary vision maximally for blue light..^[26] A potential criticism that the responses could not have been due to heat would be missplaced as heat is dissipated at higher wavelengths and would cause the sensation of greatest response with long wavelength, or yellow and red, light, and not to short wavelength blue light as the workers found.

See also

• Circadian rhythm
• G protein-coupled receptor
• Sensory system
• Photosensitive
• Photosensitive ganglion cell
• Horizontal cell
• Bipolar cell
• Amacrine cell
• Ganglion cell

Bibliography

• Campbell, Neil A., and Reece, Jane B. (2002). Biology. San Francisco: Benjamin Cummings, 1064-1067. ISBN 0-8053-6624-5. 

• Freeman, Scott (2002). Biological Science (2nd Edition). Englewood Cliffs, N.J: Prentice Hall, 835-837. ISBN 0-13-140941-7. 

References