The novel product of a five-exon stargazin-related gene abolishes CaV2.2 calcium channel expression

Moss, Fiona; Viard, Patricia; Davies, Anthony; Bertaso, Federica; Page, Karen M.; Graham, Alex; Cantı́, Carles; Plumpton, Mary; Plumpton, Christopher; Clare, Jeffrey J.; Dolphin, Annette

doi:10.1093/emboj/21.7.1514

Cited by 82 publications

(78 citation statements)

References 36 publications

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“…One previously characterized role of Stargazin and related proteins in calcium channel modulation is their inhibitory effect on current amplitude and expression of the channels. 7,9,10 In accordance with the above reports, our study showed that coexpression of Stargazin with the Ca V 2.2 channel inhibited current amplitudes, and coexpression of Stargazin and Ca V 2.2 containing YFPtagged α 1B subunit (YFP-α 1B ), decreased channel surface expression. This inhibitory effect seemed independent of Gβγ, as Stargazin decreased channel expression in oocytes with or without coexpressed Gβγ.…”

supporting

confidence: 91%

“…[5][6][7] Later studies revealed that Stargazin is a crucial regulator of AMPA receptors. 8 Still, Stargazin and other γ proteins were found to inhibit calcium channel currents and expression, 9,10 while their effect on channel's biophysical properties remained debated. 7,9,[11][12][13][14] We have recently discovered that Stargazin modulation of Ca V 2.2 channels coexpressed in Xenopus oocytes is dependent on the G protein βγ subunit.…”

mentioning

confidence: 99%

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Further characterization of regulation of Ca_V2.2 by Stargazin

Tselnicker¹,

Dascal²

2010

Channels

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supporting

confidence: 91%

mentioning

confidence: 99%

Further characterization of regulation of Ca_V2.2 by Stargazin

Tselnicker¹,

Dascal²

2010

Channels

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“…In the recent past, a number of ␥ subunits that are expressed in a variety of tissues have been cloned (13)(14)(15)(16), and their functional roles are only beginning to be revealed. In general, the ␥ subunits appear to be inhibitory (7,22,30,34). The important physiological role for the ␥ subunit is emphasized by the epileptic phenotype in the stargazer mouse, a spontaneous mutant that lacks the ␥ 2 subunit (13).…”

Section: Discussionmentioning

confidence: 99%

γ1 Subunit Interactions within the Skeletal Muscle L-type Voltage-gated Calcium Channels

Arikkath

Chen

Ahern

et al. 2003

Journal of Biological Chemistry

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Voltage-gated calcium channels mediate excitationcontraction coupling in the skeletal muscle. Their molecular composition, similar to neuronal channels, includes the pore-forming ␣ 1 and auxiliary ␣ 2 ␦, ␤, and ␥ subunits. The ␥ subunits are the least characterized, and their subunit interactions are unclear. The physiological importance of the neuronal ␥ is emphasized by epileptic stargazer mice that lack ␥ 2 . In this study, we examined the molecular basis of interaction between skeletal ␥ 1 and the calcium channel. Our data show that the ␣ 1 1.1, ␤ 1a , and ␣ 2 ␦ subunits are still associated in ␥ 1 null mice. Reexpression of ␥ 1 and ␥ 2 showed that ␥ 1 , but not ␥ 2 , incorporates into ␥ 1 null channels. By using chimeric constructs, we demonstrate that the first half of the ␥ 1 subunit, including the first two transmembrane domains, is important for subunit interaction. Interestingly, this chimera also restores calcium conductance in ␥ 1 null myotubes, indicating that the domain mediates both subunit interaction and current modulation. To determine the subunit of the channel that interacts with ␥ 1 , we examined the channel in muscular dysgenesis mice. Cosedimentation experiments showed that ␥ 1 and ␣ 2 ␦ are not associated. Moreover, ␣ 1 1.1 and ␥ 1 subunits form a complex in transiently transfected cells, indicating direct interaction between the ␥ 1 and ␣ 1 1.1 subunits. Our data demonstrate that the first half of ␥ 1 subunit is required for association with the channel through ␣ 1 1.1. Because subunit interactions are conserved, these studies have broad implications for ␥ heterogeneity, function and subunit association with voltage-gated calcium channels.The L-type voltage-gated calcium channels of the skeletal muscle serve both as a voltage-gated calcium channel and as a voltage sensor for excitation-contraction (EC) 1 coupling (1, 2). These channels serve to couple depolarization to intracellular calcium release via the ryanodine receptor. The sites of EC coupling in the skeletal muscle are the triads, which are highly organized junctions comprising the t-tubules and the underlying sarcoplasmic reticulum (3). The voltage-gated calcium channels are localized predominantly in the t-tubules in close association with the ryanodine receptor in the sarcoplasmic reticulum (4, 5).At the molecular level, the calcium channel is composed of the pore-forming ␣ 1 1.1 subunit and auxiliary ␣ 2 ␦, ␤ 1 , and ␥ 1 subunits (6). This four-subunit composition of the channels is similar to that of the neuronal voltage-gated channels (7, 8). The auxiliary ␣ 2 ␦ and ␤ subunits enhance membrane trafficking of the ␣ 1 1.1 subunit and modulate the voltage-dependent kinetics of the channel (9). In addition to the role of the ␤ 1 subunit in the trafficking of the channel, it also has a crucial role in EC coupling as emphasized by the absence of EC coupling and early lethality in mice that lack the skeletal ␤ 1 subunit (10). The subunit interactions of the ␣ 2 ␦ and ␤ subunits have been relatively well defined.The ␥ 1 subunit is ...

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“…Previous studies showed that ␥-5 does not modulate AMPA receptor function in oocytes (Tomita et al, 2004). And, a preliminary characterization suggested that ␥-7 can inhibit the expression of calcium channels in oocytes or transfected cells (Moss et al, 2002). Here, we explored functional roles for ␥-5 and ␥-7 proteins, which unexpectedly define ␥-7 as a new member of the TARP family that differentially regulates AMPA receptors.…”

Section: Introductionmentioning

confidence: 92%

New Transmembrane AMPA Receptor Regulatory Protein Isoform, γ-7, Differentially Regulates AMPA Receptors

Kato¹,

Zhou²,

Milstein³

et al. 2007

J. Neurosci.

128

168

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AMPA-type glutamate receptors (GluRs) mediate most excitatory signaling in the brain and are composed of GluR principal subunits and transmembrane AMPA receptor regulatory protein (TARP) auxiliary subunits. Previous studies identified four mammalian TARPs, ␥-2 (or stargazin), ␥-3, ␥-4, and ␥-8, that control AMPA receptor trafficking, gating, and pharmacology. Here, we explore roles for the homologous ␥-5 and ␥-7 proteins, which were previously suggested not to serve as TARPs. Western blotting reveals high levels of ␥-5 and ␥-7 in the cerebellum, where ␥-7 is enriched in Purkinje neurons in the molecular layer and glomerular synapses in the granule cell layer. Immunoprecipitation proteomics shows that cerebellar ␥-7 avidly and selectively binds to AMPA receptor GluR subunits and also binds to the AMPA receptor clustering protein, postsynaptic density-95 (PSD-95). Furthermore, ␥-7 occurs together with PSD-95 and AMPA receptor subunits in purified postsynaptic densities. In heterologous cells, ␥-7 but not ␥-5 greatly enhances AMPA receptor glutamateevoked currents and modulates channel gating. In granule cells from stargazer mice, transfection of ␥-7 but not ␥-5 increases AMPA receptor-mediated currents. Compared with stargazin, ␥-7 differentially modulates AMPA receptor glutamate affinity and kainate efficacy. These studies define ␥-7 as a new member of the TARP family that can differentially influence AMPA receptors in cerebellar neurons.

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The novel product of a five-exon stargazin-related gene abolishes CaV2.2 calcium channel expression

Cited by 82 publications

References 36 publications

Further characterization of regulation of Ca_V2.2 by Stargazin

Further characterization of regulation of Ca_V2.2 by Stargazin

γ1 Subunit Interactions within the Skeletal Muscle L-type Voltage-gated Calcium Channels

New Transmembrane AMPA Receptor Regulatory Protein Isoform, γ-7, Differentially Regulates AMPA Receptors

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The novel product of a five-exon stargazin-related gene abolishes CaV2.2 calcium channel expression

Cited by 82 publications

References 36 publications

Further characterization of regulation of CaV2.2 by Stargazin

Further characterization of regulation of CaV2.2 by Stargazin

γ1 Subunit Interactions within the Skeletal Muscle L-type Voltage-gated Calcium Channels

New Transmembrane AMPA Receptor Regulatory Protein Isoform, γ-7, Differentially Regulates AMPA Receptors

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Further characterization of regulation of Ca_V2.2 by Stargazin

Further characterization of regulation of Ca_V2.2 by Stargazin