Modulation of Basal and Receptor-Induced GIRK Potassium Channel Activity and Neuronal Excitability by the Mammalian PINS Homolog LGN

Wiser, Ofer; Xiang, Qian; Ehlers, Melissa L.; Ja, William W.; Roberts, Richard W.; Reuveny, Eitan; Jan, Yuh Nung

doi:10.1016/j.neuron.2006.03.046

Cited by 56 publications

(54 citation statements)

References 70 publications

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“…In contrast, currents in cells expressing GABA B R and Girk2 were small. Consistent with previous observations (11,12), pretreatment of cells expressing the Girk1/Girk2 heteromer with pertussis toxin, which uncouples Gi/o G proteins from activated receptors, eliminated the baclofen-induced but not basal current (Fig. 1B).…”

Section: Resultssupporting

confidence: 92%

Structural elements in the Girk1 subunit that potentiate G protein–gated potassium channel activity

Wydeven

Young

Mirkovic

et al. 2012

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

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G protein-gated inwardly rectifying K + (Girk/K IR 3) channels mediate the inhibitory effect of many neurotransmitters on excitable cells. Girk channels are tetramers consisting of various combinations of four mammalian Girk subunits (Girk1 to -4). Although Girk1 is unable to form functional homomeric channels, its presence in cardiac and neuronal channel complexes correlates with robust channel activity. This study sought to better understand the potentiating influence of Girk1, using the GABA B receptor and Girk1/Girk2 heteromer as a model system. Girk1 did not increase the protein levels or alter the trafficking of Girk2-containing channels to the cell surface in transfected cells or hippocampal neurons, indicating that its potentiating influence involves enhancement of channel activity. Structural elements in both the distal carboxyl-terminal domain and channel core were identified as key determinants of robust channel activity. In the distal carboxyl-terminal domain, residue Q404 was identified as a key determinant of receptor-induced channel activity. In the Girk1 core, three unique residues in the pore (P) loop (F137, A142, Y150) were identified as a collective potentiating influence on both receptor-dependent and receptorindependent channel activity, exerting their influence, at least in part, by enhancing mean open time and single-channel conductance. Interestingly, the potentiating influence of the Girk1 P-loop is tempered by residue F162 in the second membrane-spanning domain. Thus, discontinuous and sometime opposing elements in Girk1 underlie the Girk1-dependent potentiation of receptor-dependent and receptor-independent heteromeric channel activity.ion channel | electrophysiology | mutagenesis | baclofen

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Section: Resultssupporting

confidence: 92%

Structural elements in the Girk1 subunit that potentiate G protein–gated potassium channel activity

Wydeven

Young

Mirkovic

et al. 2012

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

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“…Several previous studies have implicated mPins in tuning synaptic plasticity via regulating the trafficking of NMDA receptor or the activity of G protein-activated inwardly rectifying potassium channels in hippocampal neurons (17,39). Our current findings raise the exciting possibility that AGS3 and mPins may constitute a family of important modulators of neural plasticity.…”

Section: Discussionsupporting

confidence: 52%

A specific role of AGS3 in the surface expression of plasma membrane proteins

Groves

Gong

et al. 2007

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

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Activator of G protein signaling 3 (AGS3), originally identified in a functional screen for mammalian proteins that activate heterotrimeric G protein signaling, is known to be involved in drug-seeking behavior and is up-regulated during cocaine withdrawal in animal models. These observations indicate a potential role for AGS3 in the formation or maintenance of neural plasticity. We have found that the overexpression of AGS3 alters the surface-to-total ratios of a subset of heterologously expressed plasma membrane receptors and channels. Further analysis of the endocytic trafficking of one such protein by a biotin-based internalization assay suggests that overexpression of AGS3 moderately affects the internalization or recycling of surface proteins. Moreover, AGS3 overexpression and siRNA-mediated knockdown of AGS3 both result in the dispersal of two endogenously expressed trans-Golgi network (TGN)-associated cargo proteins without influencing those in the cis-or medial-Golgi compartments. Finally, adding a TGN-localization signal to a CD4-derived reporter renders the trafficking of fusion protein sensitive to AGS3. Taken together, our data support a model wherein AGS3 modulates the protein trafficking along the TGN/plasma membrane/endosome loop. drug addiction ͉ Golgi apparatus ͉ membrane trafficking ͉ receptors and channels

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“…Correspondingly, DL-G1/G2 and G1/DL-G2 expressed alone at high levels yield high I basal (10) and an intermediate i-FRET signal. A substantial basal GIRK activity has been reported in hippocampal and cortical neurons (31,32); therefore, the preactivated states are physiologically relevant.…”

Section: G␤␥ Is Crucial For Strong Interaction Between Girk1mentioning

confidence: 99%

Gαi and Gβγ Jointly Regulate the Conformations of a Gβγ Effector, the Neuronal G Protein-activated K+ Channel (GIRK)

Berlin

Keren-Raifman

Castel

et al. 2010

Journal of Biological Chemistry

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Stable complexes among G proteins and effectors are an emerging concept in cell signaling. The prototypical G␤␥ effector G protein-activated K ؉ channel (GIRK; Kir3) physically interacts with G␤␥ but also with G␣ i/o . Whether and how G␣ i/o subunits regulate GIRK in vivo is unclear. We studied triple interactions among GIRK subunits 1 and 2, G␣ i3 and G␤␥. We used in vitro protein interaction assays and in vivo intramolecular Förster resonance energy transfer (i-FRET) between fluorophores attached to N and C termini of either GIRK1 or GIRK2 subunit. We demonstrate, for the first time, that G␤␥ and G␣ i3 distinctly and interdependently alter the conformational states of the heterotetrameric GIRK1/2 channel. Biochemical experiments show that G␤␥ greatly enhances the binding of GIRK1 subunit to G␣ i3 GDP and, unexpectedly, to G␣ i3 GTP . i-FRET showed that both G␣ i3 and G␤␥ induced distinct conformational changes in GIRK1 and GIRK2. Moreover, GIRK1 and GIRK2 subunits assumed unique, distinct conformations when coexpressed with a "constitutively active" G␣ i3 mutant and G␤␥ together. These conformations differ from those assumed by GIRK1 or GIRK2 after separate coexpression of either G␣ i3 or G␤␥. Both biochemical and i-FRET data suggest that GIRK acts as the nucleator of the GIRK-G␣-G␤␥ signaling complex and mediates allosteric interactions between G␣ i GTP and G␤␥. Our findings imply that G␣ i/o and the G␣ i ␤␥ heterotrimer can regulate a G␤␥ effector both before and after activation by neurotransmitters.It is believed that signaling via G protein-coupled receptors (GPCRs) 5 occurs within multiprotein complexes that include GPCRs, G proteins, and effectors (1-3). The G protein-activated K ϩ channel (GIRK, Kir3), an important mediator of neuronal inhibition (4), is activated by the binding of G␤␥ to the cytosolic N and C termini (NT and CT, respectively) of GIRK. G␤␥ associates with the channel before and after receptor activation (5, 6). GIRK NT and CT segments also bind G␣ i/o (see Ref. 7), but it is not clear whether and how G␣ i/o regulates GIRK in vivo. G␣ clearly plays a role in determining specificity of signaling from GPCR to GIRK (8, 9). In heterologous systems, expression of G␣ i reduces GIRK basal activity (I basal ) and increases the relative extent of activation by added or coexpressed G␤␥ (10 -12). Recently, we have demonstrated that this regulation is exerted by the GDP-bound form of G␣ i , G␣ i GDP (12); no role for G␣ i GTP in GIRK gating could be assigned so far. We proposed that regulation of GIRK by G␣ i relies upon the formation of the G␣ i GDP -G␤␥ heterotrimer, which forms a persistent, dynamic signaling complex with GIRK to ensure proper gating with low I basal and high signal-to-background ratio upon G␤␥ activation (11,12).We hypothesized that within a multiprotein signaling complex, the partner proteins alter each other's conformation and activity at various stages of the signaling process. Thus, G␣ i and G␤␥ may regulate the conformation of the channel both before and after activation. ...

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Modulation of Basal and Receptor-Induced GIRK Potassium Channel Activity and Neuronal Excitability by the Mammalian PINS Homolog LGN

Cited by 56 publications

References 70 publications

Structural elements in the Girk1 subunit that potentiate G protein–gated potassium channel activity

Structural elements in the Girk1 subunit that potentiate G protein–gated potassium channel activity

A specific role of AGS3 in the surface expression of plasma membrane proteins

Gαi and Gβγ Jointly Regulate the Conformations of a Gβγ Effector, the Neuronal G Protein-activated K+ Channel (GIRK)

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