Targeting of RGS7/Gβ5 to the Dendritic Tips of ON-Bipolar Cells Is Independent of Its Association with Membrane Anchor R7BP

Cao, Yan; Song, Hailong; Okawa, Haruhisa; Sampath, Alapakkam P.; Sokolov, Maxim; Martemyanov, Kirill A.

doi:10.1523/jneurosci.3282-08.2008

Cited by 48 publications

(57 citation statements)

References 28 publications

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“…1B), suggesting the essential role of the association with RGS for the stability of this protein. Knockout of RGS7 also resulted in destabilization of R7BP, confirming the idea that both proteins exist in a complex in ON-BC dendrites (16). Importantly, knockout of RGS7 did not affect the expression of any other proteins essential for ON-BC light-evoked signaling (Fig.…”

Section: Resultssupporting

confidence: 72%

Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons

Cao

Pahlberg²,

Sarria³

et al. 2012

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

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The time course of signaling via heterotrimeric G proteins is controlled through their activation by G-protein coupled receptors and deactivation through the action of GTPase accelerating proteins (GAPs). Here we identify RGS7 and RGS11 as the key GAPs in the mGluR6 pathway of retinal rod ON bipolar cells that set the sensitivity and time course of light-evoked responses. We showed using electroretinography and single cell recordings that the elimination of RGS7 did not influence dark-adapted light-evoked responses, but the concurrent elimination of RGS11 severely reduced their magnitude and dramatically slowed the onset of the response. In RGS7/RGS11 double-knockout mice, light-evoked responses in rod ON bipolar cells were only observed during persistent activation of rod photoreceptors that saturate rods. These observations are consistent with persistently high G-protein activity in rod ON bipolar cell dendrites caused by the absence of the dominant GAP, biasing TRPM1 channels to the closed state.vision | retina | RGS proteins | signal transduction | synaptic transmission

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Section: Resultssupporting

confidence: 72%

Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons

Cao

Pahlberg²,

Sarria³

et al. 2012

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

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“…2A), R7BP ablation did not affect expression or plasma membrane localization of RGS7 in hippocampal neurons ( Fig. 2 A and B), consistent with prior evidence that the absence of R7BP has an insignificant effect on membrane localization of RGS7 (29). R7BP therefore is likely to regulate GIRK currents by mechanisms other than anchoring R7-RGS/Gβ5 complexes to the plasma membrane.…”

Section: R7bp Allosterically Regulates Assembly Of R7-rgs/gβ5supporting

confidence: 87%

GIRK channel modulation by assembly with allosterically regulated RGS proteins

Zhou¹,

Chisari

Raehal

et al. 2012

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

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G-protein-activated inward-rectifying K + (GIRK) channels hyperpolarize neurons to inhibit synaptic transmission throughout the nervous system. By accelerating G-protein deactivation kinetics, the regulator of G-protein signaling (RGS) protein family modulates the timing of GIRK activity. Despite many investigations, whether RGS proteins modulate GIRK activity in neurons by mechanisms involving kinetic coupling, collision coupling, or macromolecular complex formation has remained unknown. Here we show that GIRK modulation occurs by channel assembly with R7-RGS/ Gβ5 complexes under allosteric control of R7 RGS-binding protein (R7BP). Elimination of R7BP occludes the Gβ5 subunit that interacts with GIRK channels. R7BP-bound R7-RGS/Gβ5 complexes and Gβγ dimers interact noncompetitively with the intracellular domain of GIRK channels to facilitate rapid activation and deactivation of GIRK currents. By disrupting this allosterically regulated assembly mechanism, R7BP ablation augments GIRK activity. This enhanced GIRK activity increases the drug effects of agonists acting at Gprotein-coupled receptors that signal via GIRK channels, as indicated by greater antinociceptive effects of GABA(B) or μ-opioid receptor agonists. These findings show that GIRK current modulation in vivo requires channel assembly with allosterically regulated RGS protein complexes, which provide a target for modulating GIRK activity in neurological disorders in which these channels have crucial roles, including pain, epilepsy, Parkinson's disease and Down syndrome. Many neurotransmitters, therapeutic agents, and drugs of abuse activate metabotropic receptors coupled to the Gi/o family of heterotrimeric G proteins. These agonists modulate neuronal excitability and synaptic transmission in part by activating G-protein-activated inward-rectifying K + channels (GIRKs or Kir3s) to hyperpolarize neurons (1). The importance of this mechanism is illustrated by the diverse phenotypes exhibited by mice lacking GIRK channel subtypes, including reduced anxiety (GIRK1) (2), hyperactivity (GIRK2) (3), propensity for seizures (GIRK2) (4), and decreased morphine-mediated analgesia (GIRK2/3) (5, 6). Conversely, augmentation of GIRK activity caused by trisomic expression of the GIRK2 gene (Kcnj6) causes cognitive impairment and other phenotypes in mouse models of Down syndrome (7-9).GIRK activity is controlled in vivo by the regulator of G protein signaling (RGS) family (10-13). Regulator of G-protein signaling (RGS) proteins accelerate rates of G-protein deactivation by acting as GTPase-activating proteins (GAPs) for Gprotein α-subunits (14-16). Thus, rapid deactivation of GIRK currents requires RGS proteins because GAP activity accelerates the rate that Gi/oα subunits hydrolyze GTP and reform inactive GDP-bound Gαβγ heterotrimers.RGS proteins have been suggested to regulate GIRK gating kinetics by several mechanisms, including kinetic coupling, collisional coupling, and macromolecular complex formation with GIRK channels. Complex formation between GIRK channels ...

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“…In this retina, the genetic composition of the rod bipolar machinery is intact, yet the mGluR6-related cascade proteins are incorrectly localized due to lack of photoreceptor input, and the rod bipolar cell remains hyperpolarized (Borowska et al 2011;Strettoi and Pignatelli 2000). Since perturbation of the rod-to-rod bipolar synapse leads to dispersion of several cascade proteins, including G␤ 5 , RGS11, and RGS7 (Cao et al 2008), the factor or protein that is crucial is not clear. This theory, however, does not exclude the possibility that during development the channels were initially open, but a constant influx of calcium desensitizes them, as has been suggested to occur during light adaptation (Shiells and Falk 1999).…”

Section: Discussionmentioning

confidence: 99%

mGluR6 deletion renders the TRPM1 channel in retina inactive

Dhingra

Fina

et al. 2012

Journal of Neurophysiology

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In darkness, glutamate released from photoreceptors activates the metabotropic glutamate receptor 6 (mGluR6) on retinal ON bipolar cells. This activates the G protein G o , which then closes transient receptor potential melastatin 1 (TRPM1) channels, leading to cells' hyperpolarization. It has been generally assumed that deleting mGluR6 would render the cascade inactive and the ON bipolar cells constitutively depolarized. Here we show that the rod bipolar cells in mGluR6-null mice were hyperpolarized. The slope conductance of the current-voltage curves and the current noise were smaller than in wild type. Furthermore, while in wild-type rod bipolar cells, TRPM1 could be activated by local application of capsaicin; in null cells, it did not. These results suggest that the TRPM1 channel in mGluR6-null rod bipolar cells is inactive. To explore the reason for this lack of activity, we tested if mGluR6 deletion affected expression of cascade components. Immunostaining for G protein subunit candidates G␣ o , G␤ 3 , and G␥ 13 showed no significant changes in their expression or distribution. Immunostaining for TRPM1 in the dendritic tips was greatly reduced, but the channel was still present in the soma and primary dendrites of mGluR6-null bipolar cells, where a certain fraction of TRPM1 appears to localize to the plasma membrane. Consequently, the lack of TRPM1 activity in the null retina is unlikely to be due to failure of the channels to localize to the plasma membrane. We speculate that, to be constitutively active, TRPM1 channels in ON bipolar cells have to be in a complex, or perhaps require an unidentified factor. rod bipolar; metabotropic glutamate receptor 6-null; G protein cascade; transient receptor potential melastatin 1; regulator of G protein signaling IN RETINA, AN INCREMENT OF light intensity hyperpolarizes the photoreceptor and sets off two opposing signals in the OFF and ON bipolar cells. In darkness, glutamate released by photoreceptors depolarizes OFF bipolar cells and hyperpolarizes ON bipolar cells. The key steps in this ON bipolar cell "sign inverting" cascade are as follows: glutamate activates the metabotropic glutamate receptor 6 (mGluR6) (Akazawa et al.

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Targeting of RGS7/Gβ5 to the Dendritic Tips of ON-Bipolar Cells Is Independent of Its Association with Membrane Anchor R7BP

Abstract: Complexes of regulator of G-protein signaling (RGS) proteins with G-protein

Cited by 48 publications

References 28 publications

Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons

Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons

GIRK channel modulation by assembly with allosterically regulated RGS proteins

mGluR6 deletion renders the TRPM1 channel in retina inactive

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