Persistent Sodium Currents through Brain Sodium Channels Induced by G Protein βγ Subunits

Jenny, Y. Y. Ooi; Catterall, William A.; Scheuer, Todd

doi:10.1016/s0896-6273(00)80952-6

Cited by 128 publications

(86 citation statements)

References 55 publications

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“…The G o protein binding domain in the intracellular domain of APP is known to selectively activate the heterotrimeric G protein G o (8 -10). Although G protein modulation of Nav1.6 has not been reported previously, our findings are consistent with G proteinmediated modulation of various other sodium channels (37)(38)(39). The increase in cell surface expression was dependent upon phosphorylation of APP695 at Thr-668.…”

Section: Discussionsupporting

confidence: 92%

“…APP-mediated Increases in Nav1.6 Cell Surface Expression Are G Protein-dependent-Various sodium channels are modulated by G proteins (37)(38)(39). To investigate whether a G o protein-linked mechanism could contribute to the increase in Nav1.6 surface expression on overexpression of APP, we conducted experiments in HEK293 Nav1.6 cells, which have strong endogenous expression of APP.…”

Section: App Is Colocalized With Nav16 In Mouse Cortical Neurons-mentioning

confidence: 99%

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Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

Liu

Tan

Xiao

et al. 2015

Journal of Biological Chemistry

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Background: Loss-of-function amyloid precursor protein (APP) and Nav1.6 transgenic mice share similar phenotypes. Results: APP interacts with Nav1.6 and enhances its cell surface expression through a G o -coupled JNK pathway. Conclusion: APP regulates Nav1.6 function, likely through a G o -coupled JNK pathway. Significance: This finding advances the current understanding of APP functions and has implications for novel therapies for neurodegenerative disorders.

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Section: Discussionsupporting

confidence: 92%

Section: App Is Colocalized With Nav16 In Mouse Cortical Neurons-mentioning

confidence: 99%

Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

Liu

Tan

Xiao

et al. 2015

Journal of Biological Chemistry

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“…Sodium channel activity is affected by association with the auxiliary ␤ subunits (8,9) and by direct interaction with G proteins (44). On the other hand, synaptotagmin can modulate the activity of N-type calcium channels (45).…”

Section: Discussionmentioning

confidence: 99%

Direct interaction between synaptotagmin and the intracellular loop I-II of neuronal voltage-sensitive sodium channels

Sampo

Tricaud²,

Lévêque³

et al. 2000

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

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Synaptotagmin, a synaptic vesicle protein involved in Ca 2؉ -regulated exocytosis, displayed direct high affinity interaction with neuronal sodium channels. Monoclonal antibodies directed against synaptotagmins I and II adsorbed in a concentration-dependent and -specific manner [ 3 H]saxitoxin prelabeled sodium channels extracted with detergent from nerve endings. Conversely, co-immunoprecipitation of synaptotagmin was achieved by antibodies against sodium channel subunits. Consistent with the co-immunoprecipitation assays, solubilized [ 3 H]saxitoxin-prelabeled sodium channels were trapped on immobilized maltose binding protein (MBP)-synaptotagmin I. In vitro recombinant protein assays were employed to identify the interaction site of synaptotagmin I, which was located on the cytoplasmic loop between domains I and II of the sodium channel ␣IIA subunit. The co-immunoprecipitated synaptotagmin-sodium channel complexes were found to be Ca 2؉ -dependent; this effect was mimicked by Ba 2؉ and Sr 2؉ but not Mg 2؉ . Finally the complex was shown to be distinct from the synaptotagmin-SNARE protein complex that can selectively interact with presynaptic calcium channels (N and P͞Q types). Thus, our findings demonstrate an unexpected and direct interaction between sodium channels and synaptotagmin. The Ca 2؉ -regulated association between sodium channels and a protein implicated in vesicular fusion may have intriguing consequences for the establishment and regulation of neuronal excitability. O ne of the major physiological roles of voltage-gated sodium channels is to initiate and propagate action potentials in excitable cells. In neurons, after the generation of a large transient Na ϩ current at the axon hillock͞initial segment or at the first of node Ranvier (reviewed in ref. 1), sodium channels ensure conduction along myelinated or unmyelinated fibers to nerve terminals. Sodium channels also participate in the integration of synaptic input and the modulation of firing properties and mediate the backpropagation of action potentials into the dendritic arborization, in certain types of neurons (reviewed in ref. 1). In addition, sodium channels can produce a non-inactivating Na ϩ current that only constitutes a small fraction of the total Na ϩ current but strongly affects neuronal firing properties (for a review, see ref.2).At the molecular level, sodium channels purified from rat brain nerve endings are composed of a heterotrimeric complex. The highly glycosylated ␣ subunit (260 kDa), which is the pore-forming protein, is associated noncovalently with the ␤1 subunit (36 kDa), and with the ␤2 subunit (33 kDa) via disulfide bonds (for a review, see ref.3). At least four genes encoding distinct ␣ subtypes that are mainly expressed in the central nervous system have been identified: ␣I and ␣II͞␣IIA (4, 5), ␣III (6), and ␣6 (7). In contrast, each auxiliary subunit is encoded by a single gene (8,9).In nerve terminals, the arrival of the depolarizing wave triggers the opening of presynaptic N-and P͞Q type calcium channels, produ...

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“…A motif, QXXER, present in the G␤␥ effectors adenylyl cyclase II and Ca 2ϩ and Na ϩ channels may specify their interaction with ␤␥ subunits (32,33). However, no such motif occurs in RGS3.…”

Section: Fig 7 Rgs3 Possesses Two Binding Sites For G␤␥mentioning

confidence: 99%

Regulator of G-protein Signaling 3 (RGS3) Inhibits Gβ1γ2-induced Inositol Phosphate Production, Mitogen-activated Protein Kinase Activation, and Akt Activation

Shi

Lee

Sinnarajah

et al. 2001

Journal of Biological Chemistry

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Regulator of G-protein signaling 3 (RGS3) enhances the intrinsic rate at which G␣ i and G␣ q hydrolyze GTP to GDP, thereby limiting the duration in which GTP-G␣ i and GTP-G␣ q can activate effectors. Since GDP-G␣ subunits rapidly combine with free G␤␥ subunits to reform inactive heterotrimeric G-proteins, RGS3 and other RGS proteins may also reduce the amount of G␤␥ subunits available for effector interactions. Although RGS6, RGS7, and RGS11 bind G␤ 5 in the absence of a G␥ subunit, RGS proteins are not known to directly influence G␤␥ signaling. Here we show that RGS3 binds G␤ 1 ␥ 2 subunits and limits their ability to trigger the production of inositol phosphates and the activation of Akt and mitogen-activated protein kinase. Co-expression of RGS3 with G␤ 1 ␥ 2 inhibits G␤ 1 ␥ 2 -induced inositol phosphate production and Akt activation in COS-7 cells and mitogen-activated protein kinase activation in HEK 293 cells. The inhibition of G␤ 1 ␥ 2 signaling does not require an intact RGS domain but depends upon two regions in RGS3 located between acids 313 and 390 and between 391 and 458. Several other RGS proteins do not affect G␤ 1 ␥ 2 signaling in these assays. Consistent with the in vivo results, RGS3 inhibits G␤␥-mediated activation of phospholipase C␤ in vitro. Thus, RGS3 may limit G␤␥ signaling not only by virtue of its GTPase-activating protein activity for G␣ subunits, but also by directly interfering with the activation of effectors.Heterotrimeric G-proteins link seven transmembrane receptors to downstream signaling pathways. Receptor activation triggers the exchange of GTP for GDP by the G␣ subunit of the heterotrimeric G-protein, causing a conformational change in the G␣ subunit, which facilitates its dissociation from the receptor and G␤␥ subunits. GTP-bound G␣ and free G␤␥ subunits then bind and activate downstream effectors. However, G␣ subunits possess an intrinsic GTPase activity, which returns G␣ to its GDP bound state and thereby limits the duration of G␣ signaling. Because GDP-G␣ possesses a high affinity for G␤␥ subunits, the heterotrimeric G-protein rapidly reforms, effectively ending G␤␥-mediated signaling as well (reviewed in Refs. 1 and 2).Cells possess another important mechanism that curtails the duration in which a G␣ subunit remains GTP bound. Members of a family of proteins termed regulators of G-protein signaling (RGS) 1 dramatically accelerate the intrinsic rate that certain G␣ subunits hydrolyze GTP, a property that identifies them as GTPase-activating proteins (GAPs). The mammalian RGS proteins have a 120-amino acid region, RGS domain, or RGS box, which binds G␣ i and G␣ q subfamily members in a transition state of the GTP hydrolysis reaction, thereby lowering the free energy of the reaction (reviewed in Refs. 3 and 4). In addition, Rho guanine nucleotide exchange factors have a divergent RGS domain, which accelerates the intrinsic GTPase activity of G␣ 12 and G␣ 13 (5, 6). RGS proteins with GAP activity for members of the G␣ s subfamily remain enigmatic.The mammalian RGS proteins ca...

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Persistent Sodium Currents through Brain Sodium Channels Induced by G Protein βγ Subunits

Cited by 128 publications

References 55 publications

Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

Direct interaction between synaptotagmin and the intracellular loop I-II of neuronal voltage-sensitive sodium channels

Regulator of G-protein Signaling 3 (RGS3) Inhibits Gβ1γ2-induced Inositol Phosphate Production, Mitogen-activated Protein Kinase Activation, and Akt Activation

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