Photosensitive cells
The visual cycle is a cycle of complex chemical reactions that enable us to perceive the sense of light. Light is focused on the retina of the eye with the aid of the lens. The retina contains the photosensitive cells – rods and cones. The retina, in fact, acts as a transducer; converting photons of light into neural signals which can then by integrated, and interpreted by the brain. The final image is integrated in a region of the brain called the visual cortex. The complex reactions that enable us to see occur, literally, in a fraction of a second.
Though vision is classified as central and peripheral, it can also be classified roughly on the availability of light. There is vision in light, when one can perceive colors of varying intensities. In fact, light of different wavelengths and frequencies can be perceived. The cells of light vision, the cone cells are adapted for high-acuity and precision. Night vision though, is what one can see in the dark. The rod cells that enable us to see in the dark though are much more sensitive to light than the cones, but do not produce as acute an image as the cones.
The image produced by the rod cells is also called ‘monochromatic vision,’ while the image produced by the cone cells is also called ‘color vision. ’ Night vision is defined as the ability to see in the dark. But there are several different reactions that make this possible. In night vision the visual compound ‘rhodopsin,’ popularly known as ‘visual purple,’ undergoes changes, enabling us to perceive light. Rhodopsin consists of a protein part, called opsin which is covalently bound to retinal – the cofactor. Opsins are a group of photosensitive ‘membrane-bound G protein-coupled receptors.
’ These receptors are a large family of receptors, protein in nature. They sense signals outside the cell, but initiate intracellular responses. Opsins are found in the photosensitive cells of the retina – the rod and cone cells. There are five known groups of opsins that participate in vision. Rhodopsin is present in the rod cells, while the other four groups are present in cone cells, and are called ‘photopsins’ or ‘iodopsins. ’ “Any one cone cell contains only one type of opsin and is sensitive to only one colour [1]. ” The cone opsins are further classified according to their absorption spectra.
Chemically too they are identical expect for a few amino acids. These pigments are most abundant in the cone cells of the retina. Rhodopsin is the characteristic visual pigment enabling one to see in the dark, present abundantly in the rod cells. In fact, Rhodopsins are very sensitive to light. The opsins in cone cells are employed in perceiving color, and are not as sensitive as the rhodopsins, even though they are responsible, as stated earlier, for visual acuity. Structurally, opsins are a group of seven transmembrane helices, with retinal bound in the centre. Retinal is a derivative of Vitamin A, produced in the retina.
This is why vitamin A is cardinal for vision in the dark. In fact, vitamin A deficiency produces characteristic night blindness. The retinal in rhodopsin is in the 11-cis form. First, retinol, obtained from the diet, in the trans form is isomerized to the 11-cis retinol form. The 11-cis retinol is then oxidized to form 11-cis retinaldehyde. The 11-cis retinal then reacts with a “lysine residue in opsin, forming the holoprotein rhodopsin [1]. ” When this pigment is exposed to light, a series of reactions occur. These are ‘photochemical isomerizations’ that result in the ‘bleaching’ of rhodopsin.
A photon of light is absorbed, and converted into an electrochemical signal, while 11-cis retinal is isomerized to all trans form. In the cis configuration, both the hydrogen atoms of a double bond are on the same side of the double bond. In the trans configuration though, the hydrogens are on opposite sides. When a molecule or even an atom absorbs a photon, ‘it makes a transition to a higher energy state [2]. ’ This is because it electrons move to orbits of higher energy. When 11-cis retinal absorbs light, ‘the pi part of the double bond, between carbon 11 and carbon 12, breaks, thus allowing free rotation around the bond [2].
’ This free rotation can form the trans form of the aldehyde. One of the first excited forms of rhodopsin is ‘bathorhodopsin. ’ This occurs literally within picoseconds of exposure to light. Then there are further reactions, including formation of the intermediate ‘metarhodopsin II’ initiating the second messenger response within the visual cell, and then the nerve impulse. The conformational changes in the protein can be described as follows. Rhodopsin changes to Photorhodopsin immediately upon illumination. What follows is bathorhodopsin, followed by lumirrhodopsin, metarhodopsin I and finally metarhodopsin II.
The metarhodopsin II induces the intracellular response. Transducin is the G-protein coupled with the receptor that is activated by the changes in opsin. Transducin itself consists of three subunits – alpha, beta and gamma. The alpha subunit contains a molecule of GDP – Guanosine diphosphate. Activated rhodopsin causes exchange of this GDP with GTP. This causes the alpha subunit to separate from the G-protein. The active alpha then causes increased activity of cyclic GMP Phosphodiesterase, an enzyme. The enzyme reduces the concentration of cyclic GMP, a very important second messenger.
Low concentrations of cGMP result in closure of all cGMP regulated channels, most important ones being the Na+ and Ca++ channels. The closure of these channels, especially the Na+ channels results in excessive polarization of the cell membrane, known as hyperpolarization. This complex chain of events is the ‘phototransduction cascade. ’ The hyperpolarization results in buildup of a potential difference, which is then passed on along an adjoining neuron. The neuron then carries this impulse to the brain, where the information is interpreted. The impulse is carried to the brain via the optic nerve.
The events are reversed when Transducin bound with GTP is hydrolyzed back to Transducin bound with GDP. Finally opsin and retinal, in the trans form are released. Briefly, the isomerization induces a change in opsin, which triggers a second messenger response in the cell, a form of signal transduction, and also, the release of opsin and all-trans retinal. But regeneration of the pigment requires isomerization of the trans retinal back to its cis form. Thus the trans retinal that is formed is isomerized back to its 11-cis form, which then combines with opsin forming rhodopsin. But complete regeneration requires almost thirty minutes.
After some time in light, rhodopsin is almost completely depleted. It is thus the rate at which the lost rhodopsin is regenerated that enables how fast one can adapt to darkness. The most important factor in the visual cycle is the availability of 11-cis retinal, and thus, in general, vitamin A. Genetic mutation remains a major reason for a number of pathological conditions of the retina, and abnormalities regarding rhodopsin. Deficiency of vitamin A though remains the leading cause of night blindness. The visual threshold is increased, thus one finds it increasingly harder to see in dim light.
Severe deficiency of the vitamin though leads to significant loss of visual cells, resulting in xerophthalmia. Anesthesiology is a field of increasing importance in medicine and surgery today. General anesthesia is essential for surgical operations, but sometimes, has profound negative effects to the extent of severe respiratory arrest or bradycardia. Thus anesthesia has to be monitored regularly. General anesthetics are administered either through inhalation, or intravenously. The most widely used inhaled anesthetics include halothane, desflurane, enflurane, isoflurane and sevoflurane.
These are, in fact, halogenated hydrocarbons that have been derived from ether itself. Intravenous anesthetics though, unlike the inhaled ones, are chemically quite unrelated. These include barbiturates, benzodiazepines, etomidate, opioids, ketamine and propofol. Ether, also known as diethyl ether, or chemically, ethoxyethane is a colorless but extremely flammable liquid with a characteristic odor. It is usually used as a solvent, but it was widely used as a general anesthetic. The first use of ether as an anesthetic goes back to 1842, when Dr. Crawford W. Long used it in a surgery. The patient felt no significant pain during the procedure.
Four years later, Dr. William Morton presented ether and its anesthetic properties at Massachusetts General Hospital. Since then, ether was established as a general anesthetic. But today, it is used in combination with used along with other anesthetics to produce ‘balanced anesthesia. ’ In fact, non-flammable agents such as halothane have largely replaced ethers. Methyl propyl ether is also used as an anesthetic agent, because of its greater effectiveness. But halogenated ethers are the modern anesthetics in use today. An ether is an organic compound with an oxygen atom connected to two alkyl groups.
In halogenated ether, one or more of the hydrogen atoms is substituted by a halogen, namely, fluorine, chlorine, bromine and iodine. Initially diethyl ether was used as an inhalation anesthetic. It proved to be quite useful, but at the same time dangerous because of its flammable nature. Often this led to explosions or fires. For some time non-flammable hydrocarbons such as chloroform were used, but these chemicals were much more hazardous, since they were toxic. Later though with more researches and advancement, halogenated ethers replaced all compounds as inhalation anesthetics.
In fact, now, all inhalation anesthetics are halogenated ethers with the exception of halothane. These compounds have the advantage of producing anesthesia, being non-flammable and having less severe side effects than the others. Diethyl ether specially, resulted in nausea and vomiting. In surgery today, anesthesia is normally administered intravenously. This produces unconsciousness in almost 25 seconds. Sometimes though, anesthesia may also be induced by inhalation. Anesthesia is maintained though through inhalation. Volatile anesthetics are easy to monitor and provide good control.
After the surgery is the phase of recovery in which the anesthesia is withdrawn, and the patient is monitored until normal conscious control is established. “Of the five volatile anesthetics used in clinical practice, three are halogenated methyl ethyl ethers (enflurane [CF2HOCF2CClFH], isoflurane [CF2HOCClHCF3], desflurane [CF2HOCFHCF3]), the fourth is a methyl isopropyl ether sevoflurane (CFH2OCH[CF3]2), and the fifth, halothane (CF3CHBrCl), is an alkane [4]. ” But what are the properties that cause anesthetic effects? The different stages of anesthesia were first studied using ether, because of its slow onset.
Anesthesia is characterized by four separate stages. First is analgesia, which is defined as loss of pain. The patient though is conscious. The second stage is that of excitement. Often the patient exhibits violent, combative behavior. The third is that of surgical anesthesia where the respiratory rate becomes regular and muscles begin to relax. This is the functional stage at which the patient can be operated upon. The fourth and final stage is that of medullary paralysis, where there is danger of death. In fact, in this stage there is profound anesthesia of the respiratory and vasomotor centers which can be lethal.
With ether these stages are easily distinguishable, but with the more commonly used anesthetics such as halothane and enflurane etc the stages proceed so rapidly that they cannot be studied separately. The anesthetics, including ether produces decreased cerebrovascular resistance [3], resulting in increased perfusion of the brain with blood. “The inhaled anesthetics also induce bronchodilation and decrease minute alveolar ventilation and pulmonary hypoxic vasoconstriction [3]. ” The movement of these compounds from the lungs to different organs depends largely upon their solubility in blood and tissues.
Rate of blood flow is also an important factor that distributes the anesthetic. Different anesthetics have different levels of potency. Potency is measured using the MAC, defined as the median alveolar concentration. MAC is roughly defined as the amount of gas in a mixture that will bring about the desired effect. Quantitatively MAC is small for effective anesthetics such as halothane, but large for other slow acting anesthetics such as nitrous oxide. As the anesthetic agent is breathed into the lungs, its movement into the blood depends on the partial pressures on the two sides.
Its movement into the lungs is called ‘alveolar wash-in. ’ The next stage is that of ‘uptake. ’ This depends on solubility of the anesthetic, cardiac output and the gradient of the anesthetic between alveolar and venous pressures. Alveolar partial pressure is the partial pressure of the anesthetic at the pulmonary capillary. The anesthetic is then distributed in the body via arteries. The partial pressure is then measured in the systemic veins. Soon a steady-state is achieved when the partial pressure in each body compartment is equal to that in the inspired mixture. Thus alveolar-venous gradient approximates.
Organs like the brain, kidney, liver and endocrine glands achieve this stead-state very fast since they have a rich blood supply. Skeletal muscles and fat tissue are slower to become anesthetized. When administration of the agent is discontinued, the body moves the anesthetic out of the body and into the alveolar space in reverse order. This stage is called ‘wash-out. ’ Thus the least soluble anesthetics exit the body faster than the more soluble ones. The mechanism of action of ether and similar inhalation anesthetics though is not well understood. So far, no receptor has been isolated.
In fact many researches and studies suggest that different compounds produce a similar state of anesthesia, ruling out the possibility of a receptor. But another mechanism of action has been studied and is widely accepted. Anesthetics are believed to increase the activity of gamma-aminobutyric acid receptors. In the absence of anesthesia, GABA binds to its receptors and this binding leads to the opening of chloride channels. This then results in hyperpolarization of the cell. But in the presence of an anesthetic, the binding of GABA to its receptors is enhanced greatly. This leads to much more increased amount of chloride entering the cell.
Thus the cell becomes excessively polarized, making it much harder to depolarize. This reduces its excitability. Similarly, other receptors are also affected by inhaled anesthetics. Mostly patients are also required to take ‘pre-anesthetic’ drugs such as barbiturates and anti-histamines to provide sedation and prevent allergic reactions. These drugs are used as an adjunct to anesthetic agents, and vary from patient to patient. They also include opioids, muscle relaxants and many different drugs.
References 1. Murray. Granner. Mayes. Rodwell. Harper’s Illustrated Biochemistry. Twenty sixth Edition. 2003. 2. Casiday, Rachel. Frey, Regina. Department of Chemistry, Washington University, “I Have Seen the Light! ” Vision and Light-Induced Molecular Changes Spectroscopy and Quantum Chemistry Experiment (http://www. chemistry. wustl. edu/~edudev/LabTutorials/Vision/Vision. html) 3. Howland, Richard D. Mycek, Mary J. Lippincott’s Illustrated Reviews: Pharmacology. Third Edition. 2006. Lippincott Williams and Wilkins. 4. Koblin. Laster. Ionescu. Gong. Eger. Halsey. Hudlicky. Polyhalogenated Methyl Ethyl Ethers: Solubilities and Anesthetic Properties. 1999. Anesthesia and Analgesia. (http://www. anesthesia-analgesia. org/cgi/content/full/88/5/1161)
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