Absence of the RGS9·Gβ5 GTPase-activating Complex in Photoreceptors of the R9AP Knockout Mouse

Keresztes, Gábor; Martemyanov, Kirill A.; Krispel, Claudia M.; Mutai, Hideki; Yoo, Peter; Maison, Stéphane F.; Burns, Marie E.; Arshavsky, Vadim Y.; Heller, Stefan

doi:10.1074/jbc.c300456200

Cited by 91 publications

(128 citation statements)

References 19 publications

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“…10a) reach approximately WT peak amplitude, and then recover along a time course about 10 times slower than WT Krispel et al, 2003;Martemyanov et al, 2003;Keresztes et al, 2004). The GCAPs−/− responses (Burns et al, 2002) rise along with the WT responses, then continue to increase to several times the peak amplitude of the WT responses.…”

Section: The Model Reproduces the Salient Features Of Genetically Modmentioning

confidence: 96%

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Toward a unified model of vertebrate rod phototransduction

et al. 2005

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Recently, we introduced a phototransduction model that was able to account for the reproducibility of vertebrate rod single-photon responses (SPRs) (Hamer et al., 2003). The model was able to reproduce SPR statistics by means of stochastic activation and inactivation of rhodopsin (R*), transducin (G α ), and phosphodiesterase (PDE). The features needed to capture the SPR statistics were (1) multiple steps of R* inactivation by means of multiple phosphorylations (followed by arrestin capping) and (2) phosphorylation dependence of the affinity between R* and the three molecules competing to bind with R* (G α , arrestin, and rhodopsin kinase). The model was also able to account for several other rod response features in the dim-flash regime, including SPRs obtained from rods in which various elements of the cascade have been genetically disabled or disrupted. However, the model was not tested under high light-level conditions. We sought to evaluate the extent to which the multiple phosphorylation model could simultaneously account for single-photon response behavior, as well as responses to high light levels causing complete response saturation and/or significant light adaptation (LA). To date no single model, with one set of parameters, has been able to do this. Dim-flash responses and statistics were simulated using a hybrid stochastic/ deterministic model and Monte-Carlo methods as in Hamer et al. (2003). A dark-adapted flash series, and stimulus paradigms from the literature eliciting various degrees of light adaptation (LA), were simulated using a full differential equation version of the model that included the addition of Ca 2+ -feedback onto rhodopsin kinase via recoverin. With this model, using a single set of parameters, we attempted to account for (1) SPR waveforms and statistics (as in Hamer et al., 2003); (2) a full darkadapted flash-response series, from dim flash to saturating, bright flash levels, from a toad rod; (3) steady-state LA responses, including LA circulating current (as in Koutalos et al., 1995) and LA flash sensitivity measured in rods from four species; (4) step responses from newt rods (Forti et al., 1989) over a large dynamic range; (5) dynamic LA responses, such as the step-flash paradigm of Fain et al. (1989), and the two-flash paradigm of Murnick and Lamb (1996); and (6) the salient response features from four knockout rod preparations. The model was able to meet this stringent test, accounting for almost all the salient qualitative, and many quantitative features, of the responses across this broad array of stimulus conditions, including SPR reproducibility. The model promises to be useful in testing hypotheses regarding both normal and abnormal photoreceptor function, and is a good starting point for development of a full-range model of cone phototransduction. Informative limitations of the model are also discussed.

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Section: The Model Reproduces the Salient Features Of Genetically Modmentioning

confidence: 96%

“…The time constant governing PDE*-inactivation [τ PDE in eqn. (A7c)] was increased by a factor of 10 Krispel et al, 2003;Martemyanov et al, 2003;Keresztes et al, 2004). (Burns et al, 2002).…”

Section: Simulation Of Other Conditionsmentioning

confidence: 99%

Toward a unified model of vertebrate rod phototransduction

et al. 2005

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“…R9AP is responsible for targeting RGS9-1 to the photoreceptor outer segment, an intracellular compartment where phototransduction takes place (5). It also determines the RGS9-1 expression level by protecting RGS9-1 from proteolytic degradation in the cell (6). Finally, R9AP enhances the ability of RGS9-1 to stimulate G protein GTPase activity thus allowing the visual signal to be terminated on the physiologically rapid time scale (5,7,8).…”

Section: Rgsmentioning

confidence: 99%

R7BP, a Novel Neuronal Protein Interacting with RGS Proteins of the R7 Family

Martemyanov

Yoo

Skiba

et al. 2005

Journal of Biological Chemistry

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136

192

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The R7 subfamily of the regulators of G protein signaling (RGS) proteins is represented by four members broadly expressed in the mammalian nervous system. Here we report that in the brain all four R7 proteins form tight complexes with a previously unidentified protein, which we call the R7-binding protein or R7BP. We initially identified R7BP as a protein co-precipitating with the R7 protein, RGS9, from extracts obtained from the striatal region of the brain. We further showed that R7BP forms a tight complex with RGS9 in vitro and that this binding occurs via the N-terminal DEP domain of RGS9. R7BP is expressed throughout the entire central nervous system but not in any of the tested nonneuronal tissues. All four R7 RGS proteins co-precipitate with R7BP from brain extracts and recombinant R7 proteins bind recombinant R7BP with high efficiency. The closest homolog of R7BP is R9AP which was previously found to interact with RGS9 in photoreceptors. Both R7BP and R9AP are related to the syntaxin subfamily of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins involved in vesicular trafficking and exocytosis. In photoreceptors R9AP regulates several critical properties of RGS9 including its intracellular targeting, stability and catalytic activity. This suggests that R7BP interactions with R7 proteins in the brain may also bear major functional significance. RGS1 proteins regulate the duration of G protein signaling by stimulating the rate of the GTP hydrolysis on G protein ␣ subunits (reviewed in Refs. 1 and 2). RGS proteins are classified in six to nine subfamilies based on the homology within the RGS catalytic domain (1-3). Most RGS proteins contain additional noncatalytic domains that modulate the properties of their catalytic domains and allow them to interact with their partners in a broad range of signaling pathways. The R7 (also called "C") subfamily of RGS proteins contains four members expressed in the mammalian nervous system, RGS6, RGS7, RGS9, and RGS11 (reviewed in Ref. 4). R7 proteins share common domain composition and exist as constitutive complexes with the type 5 G protein ␤ subunit (G␤5).Marked progress in the understanding of the function of the R7 protein came from the studies of the short splice variant of RGS9, RGS9-1, which regulates signal duration in the phototransduction pathway in vertebrate rod and cone photoreceptors. Several functional properties of RGS9-1 in photoreceptors are regulated by its interacting partner, a SNARE-like protein R9AP. R9AP is responsible for targeting RGS9-1 to the photoreceptor outer segment, an intracellular compartment where phototransduction takes place (5). It also determines the RGS9-1 expression level by protecting RGS9-1 from proteolytic degradation in the cell (6). Finally, R9AP enhances the ability of RGS9-1 to stimulate G protein GTPase activity thus allowing the visual signal to be terminated on the physiologically rapid time scale (5,7,8). RGS9-1 interaction with R9AP is mediated by the N-terminal domain of RGS9-1 c...

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“…Recordings from rods of G␤5 Ϫ/Ϫ (Krispel et al, 2003), RGS9 Ϫ/Ϫ , and R9AP Ϫ/Ϫ (RGS9 anchoring protein) (Keresztes et al, 2004) mice, which displayed similar and prolonged recovery of rod photoresponses, have established the role of G␤5-L/RGS9-1/R9AP as the GTPase accelerating protein complex (GAP) for transducin ␣-subunit (Gt␣). The GAP activity resides in the RGS domain of RGS9-1, whereas G␤5-L and R9AP confer intracellular stability, membrane affinity, and outer segment targeting modality to the complex Martemyanov et al, 2003;Keresztes et al, 2004). Because G␤5-L expression is restricted to the photoreceptors, we have further characterized the G␤5 Ϫ/Ϫ animals to study the physiological function of G␤5-S and other R7 RGS proteins.…”

Section: Introductionmentioning

confidence: 99%

Gβ5 Is Required for Normal Light Responses and Morphology of Retinal ON-Bipolar Cells

Rao¹,

Dallman²,

Henderson³

et al. 2007

J. Neurosci.

103

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G␤5 exists as two splice variants, G␤5-S and G␤5-L, which interact with and stabilize the R7 members of the regulators of G-protein signaling (RGSs): RGS6, RGS7, RGS9, and RGS11. Although the role of G␤5-L and RGS9-1 is established in photoreceptors, the physiological functions of G␤5-S and other R7 RGS proteins remain unclear. We found that the electroretinogram of G␤5 Ϫ/Ϫ mice lacks the b-wave component and that G␤5-S and RGS11 colocalize with Go␣ at the tips of the ON-bipolar cell dendrites. Unexpectedly, we found a significant reduction in the number of synaptic triads in the outer plexiform layer (OPL) of the G␤5 Ϫ/Ϫ mice, which is evident at postnatal day 14. Transgenic expression of G␤5-L in rods failed to rescue the b-wave or the OPL defects. These results indicate that G␤5-S is indispensable for OPL integrity and normal light responses of the retina.

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Absence of the RGS9·Gβ5 GTPase-activating Complex in Photoreceptors of the R9AP Knockout Mouse

Cited by 91 publications

References 19 publications

Toward a unified model of vertebrate rod phototransduction

Toward a unified model of vertebrate rod phototransduction

R7BP, a Novel Neuronal Protein Interacting with RGS Proteins of the R7 Family

Gβ5 Is Required for Normal Light Responses and Morphology of Retinal ON-Bipolar Cells

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