Arrestin Competition Influences the Kinetics and Variability of the Single-Photon Responses of Mammalian Rod Photoreceptors

Doan, Thuy; Azevedo, Anthony W.; Hurley, James B.; Rieke, Fred

doi:10.1523/jneurosci.0819-09.2009

Cited by 31 publications

(65 citation statements)

References 81 publications

(173 reference statements)

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“…In rods, the underexpression of GRK1 in GRK1 ϩ/Ϫ mice slows down the dim flash response slightly (32,33), whereas overexpression speeds it up (20,34). Surprisingly, we observed an opposite trend in cones: GRK1 ϩ/Ϫ cones displayed an acceleration of the response shutoff (Fig.…”

Section: The Expression Level Of Grk1 Modulates the Kinetics Of Conementioning

confidence: 59%

“…The essential role of GRK1 in the deactivation of rod and cone visual pigments is demonstrated by abnormally prolonged light responses in both rods and cones in GRK1 Ϫ/Ϫ animals (13,33). In mouse rods, arrestin-1 competes with GRK1 and hence modifies the GRK1 binding rate (32). Reducing the level of GRK1 in GRK1 ϩ/Ϫ rods delays termination of the dim flash response, suggesting that GRK1 binding is rate-limiting for rhodopsin deactivation.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Mammalian Cone Phototransduction by Recoverin and Rhodopsin Kinase

Sakurai

Chen

Khani

et al. 2015

Journal of Biological Chemistry

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Background: Calcium-mediated feedback to phototransduction is critical for modulating cone responses under different lighting conditions. Results: The calcium-binding protein recoverin potentiates dim light sensitivity, whereas increasing expression of its target, GRK1, delays response shutoff in cones. Conclusion: Recoverin and GRK1 levels modulate cone phototransduction. Significance: Cone pigment inactivation regulates cone responses in dim light but not in bright light.

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Section: The Expression Level Of Grk1 Modulates the Kinetics Of Conementioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Regulation of Mammalian Cone Phototransduction by Recoverin and Rhodopsin Kinase

Sakurai

Chen

Khani

et al. 2015

Journal of Biological Chemistry

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“…10. However, often an explanation of variability suppression is provided in terms of the variability of the activated complex E Ã and the number of steps to R Ã deactivation (2,4,7,16). The underlying assumption is that the variability of E Ã and its functional is essentially passed along one-to-one to that of the current and its functional.…”

Section: Resultsmentioning

confidence: 99%

“…For example the CV of the peak current amplitudes in toad is reported to be about 20% (5), and for a mouse, the CV of the area integral (integral of the relative current suppression, over the whole time course of the phenomenon), is about 36% (4). The mechanisms that ensure such a low variability of the SPR are not completely understood, and are the object of current experimental and theoretical investigation (2)(3)(4)(5)(6)(7)(8)(9)(10).…”

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confidence: 99%

Identification of key factors that reduce the variability of the single photon response

Caruso

Bisegna

Andreucci

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Rod photoreceptors mediate vision in dim light. Their biological function is to discriminate between distinct, very low levels of illumination, i.e., they serve as reliable photon counters. This role requires high reproducibility of the response to a particular number of photons. Indeed, single photon responses demonstrate unexpected low variability, despite the stochastic nature of the individual steps in the transduction cascade. We analyzed individual system mechanisms to identify their contribution to variability suppression. These include: (i) cooperativity of the regulation of the second messengers; (ii) diffusion of cGMP and Ca 2þ in the cytoplasm; and (iii) the effect of highly localized cGMP hydrolysis by activated phosphodiesterase resulting in local saturation. We find that (i) the nonlinear relationships between second messengers and current at the plasma membrane, and the cGMP hydrolysis saturation effects, play a major role in stabilizing the system; (ii) the presence of a physical space where the second messengers move by Brownian motion contributes to stabilization of the photoresponse; and (iii) keeping Ca 2þ at its dark level has only a minor effect on the variability of the system. The effects of diffusion, nonlinearity, and saturation synergize in reducing variability, supporting the notion that the observed high fidelity of the photoresponse is the result of global system function of phototransduction.modeling | rhodopsin | deactivation | phosphorylation I n vertebrate retinal rod photoreceptors, light-activated rhodopsin R Ã activates dozens of G proteins (T → T Ã ) during its random lifetime, by catalyzing GDP/GTP exchange on the G protein α-subunit. Each T Ã molecule associates, one-to-one, with a catalytic subunit of the effector, forming an active T Ã -E complex, denoted by E Ã . Molecules of E Ã hydrolyze the second messenger, cGMP. Reduction of the cGMP level induces its dissociation from the cGMP-gated cation channels, causing channel closure and suppression of the inward current. This current suppression is the experimentally measured electrophysiological response, which is usually normalized by the dark current j dark , yielding the relative current suppression (1)The mechanism of R Ã deactivation contains several random components, including the random number of phosphorylations by rhodopsin kinase (RK), and the random sojourn time at each phosphorylation level. These steps regulate the number of generated E Ã molecules and, hence, the response. Because of this randomness the responses are expected to be inherently variable, in the sense that any two rhodopsin photoisomerizations yield different responses. The system would be stable if these responses are statistically close. A measure of stability is the coefficient of variation (CV), defined as the ratio of the standard deviation to the mean, calculated over a large number of signaling events and their corresponding responses. However, the measured single photon response (SPR) is highly reproducible, i.e., the coefficient of var...

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“…arrestin | GPCR | ERK | muscarinic receptor | receptor kinase A rrestin plays a fundamental role in the negative regulation of G-protein-coupled receptors (GPCRs) signaling because its binding to GPCRs hinders G-protein association with the receptors (1)(2)(3)(4)(5). Arrestin further recruits adaptor proteins and clathrin for the internalization and desensitization of the receptor (6).…”

mentioning

confidence: 99%

Muscarinic receptor regulates extracellular signal regulated kinase by two modes of arrestin binding

Jung

Kushmerick

Seo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Binding of agonists to G-protein-coupled receptors (GPCRs) activates heterotrimeric G proteins and downstream signaling. Agonistbound GPCRs are then phosphorylated by protein kinases and bound by arrestin to trigger desensitization and endocytosis. Arrestin plays another important signaling function. It recruits and regulates activity of an extracellular signal-regulated kinase (ERK) cascade. However, molecular details and timing of ERK activation remain fundamental unanswered questions that limit understanding of how arrestin-dependent GPCR signaling controls cell functions.Here we validate and model a system that tracks the dynamics of interactions of arrestin with receptors and of ERK activation using optical reporters. Our intermolecular FRET measurements in living cells are consistent with β-arrestin binding to M 1 muscarinic acetylcholine receptors (M 1 Rs) in two different binding modes, transient and stable. The stable mode persists for minutes after agonist removal. The choice of mode is governed by phosphorylation on key residues in the third intracellular loop of the receptor. We detect a similar intramolecular conformational change in arrestin in either binding mode. It develops within seconds of arrestin binding to the M 1 receptor, and it reverses within seconds of arrestin unbinding from the transient binding mode. Furthermore, we observed that, when stably bound to phosphorylated M 1 R, β-arrestin scaffolds and activates MEK-dependent ERK. In contrast, when transiently bound, β-arrestin reduces ERK activity via recruitment of a protein phosphatase. All this ERK signaling develops at the plasma membrane. In this scaffolding hypothesis, a shifting balance between the two arrestin binding modes determines the degree of ERK activation at the membrane.arrestin | GPCR | ERK | muscarinic receptor | receptor kinase A rrestin plays a fundamental role in the negative regulation of G-protein-coupled receptors (GPCRs) signaling because its binding to GPCRs hinders G-protein association with the receptors (1-5). Arrestin further recruits adaptor proteins and clathrin for the internalization and desensitization of the receptor (6). Additional functions have been suggested, with β-arrestin producing its own signaling through interactions with other effectors (7-9). For example, β-arrestin has binding sites for cRaf (MAPK kinase kinase), MEK (MAPK kinase), and ERK (MAPK) that mediate a signaling cascade for cell proliferation, cell migration, and actin dynamics after GPCR activation (10-13). Conventionally, MEK-dependent ERK signaling is described as involving GPCR-arrestin complexes on intracellular compartments such as endosomal vesicles (10, 14-16). However, whether similar complexes at the plasma membrane might trigger ERK signaling remains unknown. Electron microscope images of arrestin-receptor complexes together with modeling suggest that β-arrestin binds in two different modes, called transient binding and stable binding, to chimeric β 2 adrenergic receptors (β 2 -AR) containing the C terminus of vasopre...

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Arrestin Competition Influences the Kinetics and Variability of the Single-Photon Responses of Mammalian Rod Photoreceptors

Cited by 31 publications

References 81 publications

Regulation of Mammalian Cone Phototransduction by Recoverin and Rhodopsin Kinase

Regulation of Mammalian Cone Phototransduction by Recoverin and Rhodopsin Kinase

Identification of key factors that reduce the variability of the single photon response

Muscarinic receptor regulates extracellular signal regulated kinase by two modes of arrestin binding

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