A Retinal-Specific Regulator of G-Protein Signaling Interacts with Gα<sub>o</sub>and Accelerates an Expressed Metabotropic Glutamate Receptor 6 Cascade

Dhingra, Anuradha; Faurobert, Eva; Dascal, Nathan; Sterling, Peter; Vardi, Noga

doi:10.1523/jneurosci.0492-04.2004

Cited by 49 publications

(39 citation statements)

References 73 publications

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“…The contribution of endogenous Xenopus G proteins to our kinetic measures was eliminated by co-expressing the catalytic subunit of pertussis toxin (PTX) and by utilizing a pertussis toxin insensitive G␣ o construct, G␣ o C351A. Consistent with an earlier report (41), heterologous expression of mGluR6, PTX catalytic subunit, PTX-insensitive G␣ o C351A, and GIRK1/GIRK4 subunits allowed for the detection of inward currents through the GIRK channels (downward and upward deflections in current traces depicted in Fig. 6A) in response to mGluR6 stimulation by glutamate application and extinction upon glutamate washout (shown in black in Fig.…”

Section: R9ap Regulates Gap Activity Of Rgs11supporting

confidence: 83%

Membrane Anchor R9AP Potentiates GTPase-accelerating Protein Activity of RGS11·Gβ5 Complex and Accelerates Inactivation of the mGluR6-Go Signaling

Masuho

Celver

Kovoor

et al. 2010

Journal of Biological Chemistry

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The R7 subfamily of RGS proteins critically regulates neuronal G protein-signaling pathways that are essential for vision, nociception, motor coordination, and reward processing. A member of the R7 RGS family, RGS11, is a GTPase-accelerating protein specifically expressed in retinal ON-bipolar cells where it forms complexes with the atypical G protein ␤ subunit, G␤ 5 , and transmembrane protein R9AP. Association with R9AP has been shown to be critical for the proteolytic stability of the complex in the retina. In this study we report that R9AP can in addition stimulate the GTPase-accelerating protein activity of the RGS11⅐G␤ 5 complex at G␣ o . Single turnover GTPase assays reveal that R9AP co-localizes RGS11⅐G␤ 5 and G␣ o on the membrane and allosterically potentiates the GTPase-accelerating function of RGS11⅐G␤ 5 . Reconstitution of mGluR6-G␣ o signaling in Xenopus oocytes indicates that RGS11⅐G␤ 5 -mediated GTPase acceleration in this system requires co-expression of R9AP. The results provide new insight into the regulation of mGluR6-G␣ o signaling by the RGS11⅐G␤ 5 ⅐R9AP complex and establish R9AP as a general GTPase-accelerating protein activity regulator of R7 RGS complexes. Regulators of G protein signaling (RGS)3 are ubiquitous signaling molecules that critically shape cellular responses mediated by G protein-coupled receptor (GPCR) pathways (1). Most RGS proteins act by stimulating the rate of the GTP hydrolysis of the ␣ subunits of G proteins (G␣), thus speeding up their inactivation and limiting the duration of GPCR signaling (2). R7 subfamily of RGS proteins plays a central role in regulating fundamental neuronal functions including vision, nociception, reward processing, and motor control (3-6). The subfamily consists of four homologous proteins, RGS6, RGS7, RGS9, and RGS11, that are enriched in the nervous system and share a common multidomain architecture that, in addition to the catalytic RGS domain, includes an N-terminal DEP/DHEX (Dishevelled, EGL-10, Pleckstrin/DEP helical extension) module and a GGL (G protein ␥ subunit-like) domain (7).In vivo, R7 RGS proteins are found in complexes with two types of proteins that are becoming increasingly accepted as their subunits. The GGL forms a complex with the atypical G protein ␤ subunit, G␤ 5 (8). The DEP/DHEX module binds to either R7BP (R7 family binding protein) or R9AP (RGS9 anchor protein) (9, 10), a two-member family of small SNARE (soluble N-ethylmaleimide factor attachment protein receptor)-like proteins. Association with both G␤ 5 (11, 12) and R7BP/R9AP (13-15) protects complexes from proteolytic degradation and, thus, plays an important role in regulating the expression levels of the R7 RGS proteins. In addition, membrane proteins R9AP and R7BP can localize R7 RGS proteins to cell membranes in transfected cells and native neurons (16 -18). Finally, R9AP has been shown to enhance the GTPase-accelerating protein (GAP) activity of RGS9-1 toward transducin, suggesting that membrane anchors also play a role in regulation of R7 RGS activity (10, ...

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Section: R9ap Regulates Gap Activity Of Rgs11supporting

confidence: 83%

Membrane Anchor R9AP Potentiates GTPase-accelerating Protein Activity of RGS11·Gβ5 Complex and Accelerates Inactivation of the mGluR6-Go Signaling

Masuho

Celver

Kovoor

et al. 2010

Journal of Biological Chemistry

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“…The speculation that G␤5-S/RGS7 and/or G␤5-S/RGS11 regulates GTP hydrolysis of Go␣ is apparently at odds with the notion that Ret-RGS1 is the physiological GAP for Go␣ in the ON-bipolar cells (Dhingra et al, 2004).…”

Section: A Role Of G␤5-s and R7 Rgs Proteins In The Mglur6 Pathway Ofmentioning

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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“…To date, however, there is no functional evidence that either RGS11 or RGS7 specifically increase the rate of GTPase activity by Gαo. Another regulator of G protein signaling, ret-RGS1 has been detected in the dendrites and cell bodies of rod ON bipolar cells (Dhingra et al, 2004). Using an expression system, this group demonstrated that coexpression of ret-RGS1, along with Go and mGluR6, sped the rate at which signaling is terminated, although this rate is still quite slow compared to the rising phase of the light response.…”

Section: The Mglur6 Receptor and Its Signaling Pathwaymentioning

confidence: 99%

“…Phosphorylation by cGK could either increase the affinity of the synaptic channel for an intracellular agonist that is required for channel opening, or it could lower channel affinity for a substance that closes the channel (as is discussed in the following section). The mGluR6 receptor has been expressed in oocytes (Dhingra et al, 2004) and in superior cervical ganglion cells (Tian and Kammermeier, 2007). Thus, the question of whether cGK can functionally modulate mGluR6 can be addressed by coexpression of the receptor and cGK along with a readout channel (such as a G protein-regulated inwardly rectifying K + channel).…”

Section: Mechanism Of Cgmp Potentiationmentioning

confidence: 99%

Regulation of ON bipolar cell activity

Snellman

Kaur

Shen

et al. 2008

Progress in Retinal and Eye Research

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Synaptic transmission from photoreceptors to all types of ON bipolar cells is primarily mediated by the mGluR6 receptor. This receptor, which is apparently expressed uniquely in the nervous system by ON bipolar cells, couples negatively to a nonselective cation channel. This arrangement results in a sign reversal at photoreceptor/ON bipolar cell synapse, which is necessary in order to establish parallel ON and OFF pathways in the retina. The synapse is an important target for 2 nd messenger molecules that are known to modulate synaptic transmission elsewhere in the nervous system, 2 nd messengers that act on a time scale ranging from milliseconds to minutes. This review focuses on two of these molecules, Ca 2+ and cGMP, summarizing our current knowledge of how they modulate gain at the photoreceptor/ON bipolar cell synapse, as well as their proposed sites of action within the mGluR6 cascade. The implications of plasticity at this synapse for retinal function will also be examined.

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A Retinal-Specific Regulator of G-Protein Signaling Interacts with Gα_oand Accelerates an Expressed Metabotropic Glutamate Receptor 6 Cascade

Cited by 49 publications

References 73 publications

Membrane Anchor R9AP Potentiates GTPase-accelerating Protein Activity of RGS11·Gβ5 Complex and Accelerates Inactivation of the mGluR6-Go Signaling

Membrane Anchor R9AP Potentiates GTPase-accelerating Protein Activity of RGS11·Gβ5 Complex and Accelerates Inactivation of the mGluR6-Go Signaling

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

Regulation of ON bipolar cell activity

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A Retinal-Specific Regulator of G-Protein Signaling Interacts with Gαoand Accelerates an Expressed Metabotropic Glutamate Receptor 6 Cascade

Cited by 49 publications

References 73 publications

Membrane Anchor R9AP Potentiates GTPase-accelerating Protein Activity of RGS11·Gβ5 Complex and Accelerates Inactivation of the mGluR6-Go Signaling

Membrane Anchor R9AP Potentiates GTPase-accelerating Protein Activity of RGS11·Gβ5 Complex and Accelerates Inactivation of the mGluR6-Go Signaling

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

Regulation of ON bipolar cell activity

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A Retinal-Specific Regulator of G-Protein Signaling Interacts with Gα_oand Accelerates an Expressed Metabotropic Glutamate Receptor 6 Cascade