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Date: 03.02.2018

To the Light: Part 3 (1993)

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The resulting decrease in the cytoplasmic free cGMP concentration leads to the closure of the cGMP-gated channels on the plasma membrane. Channel closure leads to localized reduction on the influx of cations into the outer segment, which results in membrane hyperpolarization, i.

This hyperpolarization decreases or terminates the dark glutamate release at the synaptic terminal. The signal is further processed by other neurons in the retina before being transmitted to higher centers in the brain. This phototransduction cascade is shown in Figures 6 and 7. Schematic representation on the activation of vertebrate rod phototransduction. The consequent decrease in the cytoplasmic free cGMP concentration leads to the closure of the cGMP-gated channels on the plasma membrane and blockage of the influx of cations into the outer segment, which results in the reduction of the circulating dark current Following light activation, a timely recovery of the photoreceptor is essential so that it can respond to subsequently absorbed photons, and signal rapid changes in illumination see Figure 8.

This recovery from light requires the efficient inactivation of each of the activated components: The termination rates of the activation steps set the time course of the photoresponse. Recovery of rod phototransduction cascade that results in the re-openning of cGMP-gated channels on the plasma membrane from light to dark state.

Courtesy of Wolfgang Baehr Although rod phototransduction is the best characterized sensory transduction pathway, rods differ from other sensory cells in that light leads to hyperpolarization rather than depolarization. Rods respond to light with graded hyperpolarization whose amplitude increases monotonically as a function of flash intensity until saturation. One hallmark of rod phototransduction is the reproducibility of its single-photon response in both amplitude and kinetics.

This is quite remarkable considering the fact that events generated by single molecules are stochastic in nature. The study on the underlying mechanisms has long been a hot topic in the vision field.

Recent research pointed to two possible mechanisms: Averaging over the deactivation of multiple G protein molecules is important for the constancy in response decay. The details of the activation phase of rod phototransduction are now well established. A quantitative description is achieved that reproduces the activation kinetics of the rod response under physiological conditions Arshavsky et al.

We shall discuss below the major proteins mediating the activation phase in mouse rods — visual pigment, transducin, the effector PDE, and the cGMP-gated channel. The focus will be on studies with combined approaches from mouse genetics and physiology. Visual Pigments of Mouse Rods and Cones Mouse has a single rod pigment, rhodopsin, and two cone pigments: S- and M- cone pigments, with maximal spectral sensitivity at nm and nm, respectively.

Mouse is unusual in that individual cones express both S- and M-cone pigments, with the M-pigment level decreasing in a gradient from dorsal to ventral retina Applebury et al. Figure 9b Palczewski et al. The future challenge is to solve the structure of cone pigments, which is much more unstable than rhodopsin. Stereo pair of the crystal structure of rhodopsin. From Stenkamp et al.

George Wald first identified vitamin A in the retina Wald, and later showed how it functions with light, which forms the molecular basis of vision Nobel Prize The chromophore is covalently bound via a Schiff-base linkage to a conserved lysine residue K in mammalian rhodopsin in the seventh transmembrane helix Figure 9 and 9b.

In darkness, the cis-retinal acts as an inverse agonist to lock rhodopsin in an inactive state by preventing free opsin from activating the transduction cascade. RPE65 functions as an isomerase in the RPE visual cycle, which is important for regenerating rod and cone pigments. Rod photoreceptors degenerate slowly due to the constant activation of phototransduction by the large amount of free rod opsin.

In a separate experiment, K is mutated to glutamic acid, producing an opsin with no chromophore-binding site Li et al. Even with cis-retinal attached, rhodopsin occasionally undergoes spontaneous thermal activation in the dark, producing responses identical to those triggered by photons Baylor et al. Spontaneous activation of visual pigment molecules sets an ultimate limit on visual sensitivity Aho et al. In a toad rod, the rate of thermal activation of rhodopsin was measured to be 0.

This great stability makes it possible for rods to pack many rhodopsin molecules to the rod discs to increase its photon-capture ability while keeping the dark noise low. In wild-type mouse rods, it is rather difficult to measure the discrete noise arising from the thermal activation of rhodopsin because of the relatively small amplitude of the single-photon response. It should be mentioned that the question of dark noise in vision has had a long intellectual history from the point of view of psychophysics and system neuroscience.

Red cone pigment is much more prone to spontaneous isomerization than rhodopsin Kefalov et al. Thus, the overwhelming amount of dark noise in the primate red cone originates not from spontaneous isomerization of the pigment, but most probably from constitutive activity in the downstream phototransduction steps, such as the phosphodiesterase Holcman and Korenbrot, Since mammals use A1 chromophore, A1 red cone pigment is perhaps fold less prone to spontaneous isomerization than the A2 form Fu et al.

Consequently, this introduces a red shift in absorption Donner et al. Incidentally, A1 rhodopsin was found to be 30 times more stable than A2 rhodopsin, rather similar to the finding for red cone pigment Ala-Laurila et al.

More importantly, unlike in lower vertebrates such as salamander where A2 red cone pigment is sufficiently noisy as to impose a potential adaptational influence on cones even in darkness Kefalov et al. In other words, the much lower absolute sensitivity of mammalian cones compared to mammalian rods appears to arise not from quantal noise in the pigments themselves, but from other phototransduction steps Miller et al.

This may explain why primate red, green and blue cones, unlike their amphibian counterparts Ma et al. Photobleaching process of bovine rhodopsin. After photon absorption and electronic excitation, fast isomerization of the chromophore leads to the formation of a series of intermediate states of rhodopsin. The intermediate states were identified by both low-temperature and time-resolved spectroscopy.

The peak spectral sensitivity of each state was indicated. Modified from Wolfgang Baehr Photon absorption by cis-retinal triggers the cis-to-trans isomerization of the retinoid Hubbard and Wald, ; Wald, As early as in the ss, vision scientists knew that rhodopsin bleaches in stages over intermediates that were short-lived at room temperature, yet stable at low temperatures Lythgoe and Quilliam, ; Wald, ; Wald et al.

Photo-isomerization rapidly converts the ligand from a powerful inverse agonist to a powerful agonist, leading to the formation of a series of spectrally distinct intermediates of rhodopsin in the order of bathorhodopsin, lumirhodopsin, metarhodopsin I Meta I , and metarhodopsin II Meta II within a few millisecond reviewed in Okada and Palczewski, Figure The Meta-II state of cone pigment decays 50 times more rapidly than that of rhodopsin Imai et al.

Despite this difference, rhodopsin and transgenic red cone cone pigment, and vice versa, signal identically downstream when compared side-by-side in the same Xenopus rod or cone Kefalov et al. The same was found for rhodopsin and transgenic red cone pigment in mouse rod Fu et al. Schematic of the proposed proton transfer mechanism for switching the protonated Schiff-base PSB counterion in rhodopsin.

Electrostatic interaction between the PSB and Glu is indicated by the green dashed line. The gray arrows indicate a possible proton transfer pathway. The PSB group is now close to Glu to establish the electrostatic interaction green dashed line with the new counterion.

Reprinted from Yan et al. The absorption shifts into the visible region when the Schiff-base SB is protonated.

Like other vertebrate pigments, mouse rhodopsin and M-cone pigment are protonated. On the other hand, mouse S-cone pigment is unprotonated, explaining its absorption in the UV-region Vought et al.

Phototransduction in Rods and Cones by Yingbin Fu – Webvision

The positively charged Schiff-base is stabilized by the counterion E residue number according to mouse rhodopsin in rhodopsin and M-cone pigment Nathans, ; Palczewski et al. Therefore, E replaces E as the counterion to stabilize the protonated Schiff-base in the transition stage before its eventual deprotonation Yan et al. Because the mouse S-cone pigment is not protonated and the nearby E is neutral, the interesting questions are: Remarkably, after the cis isomerization, the Schiff-base picked up a proton in the Lumi state from E to become transiently protonated Dukkipati et al.

Thus, the counterion switch appears to be a general mechanism for the activation of all visual pigments. Molecular models of the lumi A and meta I B intermediates of mouse S-cone UV pigment based on the assumption that a counterion switch occurs during the lumi E counterion to meta I E counterion transformation. Reprinted from Kusnetzow et al. The all-trans chromophore is converted back to cis-retinal through a cascade of enzymatic reactions called the visual cycle in the adjacent RPE, before being used again for the regeneration of visual pigments for example, see review McBee et al.

Visual pigment is a major structural component of rods and cones. It is not surprising that genetic deletion of mouse rhodopsin results in rods without proper outer-segment formation Humphries et al. Is half the amount of normal rhodopsin enough for maintaining a healthy ROS? However, a progressive mild degeneration of the rods does occur. This finding thus would point to the diffusional encounter of transducin by photoexcited rhodopsin as the rate-limiting step in the activation of the rod photoresponse.

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However, Liang et al. High quantum efficiency of photoactivation The quantum efficiency of photoactivation measures the probability that the adsorption of a photon initiates photoactivation. This probability is defined as the ratio between the number of photoactivated molecules and the number of molecules that absorbed a photon. This suggests that every absorbed photon in the visible range can activate rhodopsin equally well.

The quantum efficiency of 0. This high efficiency seems to be a common feature of most vertebrate visual pigments.

The rate is roughly doubled in mammalian rods due to a difference in body temperature. These lipid modifications help anchor the holo-transducin to the disc membrane. It was also used successfully to delineate two apoptotic pathways in light-induced retinal degeneration Hao et al. Bright light triggers apoptosis of photoreceptors through a mechanism requiring the activation of rhodopsin but not transducin signaling. In contrast, low-intensity light induces apoptosis that is predominantly dependent on transducin signaling.

Almost two decades ago, rod transducin was found to undergo light-dependent redistribution Brann and Cohen, ; Whelan and McGinnis, Great progress has been made in the past few years by using mouse or rat models for study.

This phenomenon has been suggested to contribute to light adaptation of rods Sokolov et al. This might be consistent with the need for cones to function in bright light Elias et al. What is the significance of this difference?

The high catalytic power of PDE accounts for the second amplification step PDE is the third component of vertebrate phototransduction. PDE is anchored to the disc membrane by isoprenylation of the C-termini of the two catalytic subunits Anant et al.

Thus, the first three components of phototransduction are present in the ratio of R: However, Tsang et al.