Phosphorylation of the Synaptic Protein Interaction Site on N-type Calcium Channels Inhibits Interactions with SNARE Proteins

Yokoyama, Charles T.; Sheng, Zu Hang; Catterall, William A.

doi:10.1523/jneurosci.17-18-06929.1997

Cited by 137 publications

(111 citation statements)

References 57 publications

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“…In vitro phosphorylation assays were performed by using a recombinant active form of pp60-Src. The first half of loop II-III, the synprint region to which the SNARE-SNAP (soluble NSF attachment protein-synaptosome-associated pro- tein) receptors bind (12), was tyrosine-phosphorylated in vitro. This sequence contains 2 tyrosine residues.…”

Section: Recruitment Of Members Of the Ras Signaling Pathway To The Cmentioning

confidence: 99%

N-type Ca2+ Channels as Scaffold Proteins in the Assembly of Signaling Molecules for GABAB Receptor Effects

Richman

Tombler

Lau

et al. 2004

Journal of Biological Chemistry

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An emerging concept in signal transduction is the organization of neuronal receptors and channels into microdomains in which signaling proteins are brought together to regulate functional responses. With the multiplicity of potential protein-protein interactions arises the need for the regulation and timing of these interactions. We have identified N-type Ca 2؉ channelsignaling molecule complexes formed at different times upon activation of ␥-aminobutyric acid, type B, receptors. The first type of interaction involves pre-association of signaling proteins such as Src kinase with the Ca 2؉ channel, because it is rapidly activated by the receptors and regulates the magnitude of the inhibition of the Ca 2؉ channel. The second type of interaction involves signaling molecules that are recruited to the channel by receptor activation and control the rate of the channel response. Recruitment of members of the Ras pathway has two effects as follows: 1) modulation of the rate of onset of the ␥-aminobutyric acid-mediated inhibition of Ca 2؉ current, and 2) activation of MAP kinase. Our results suggest that the Ca 2؉ channel ␣ 1 subunit functions as a dynamic scaffold allowing assembly of intracellular signaling components that alter channel activity and route signals to the MAP kinase pathway.Voltage-dependent Ca 2ϩ channels are well known targets for inhibition by G protein-coupled receptors, and multiple pathways for inhibition have been described (1, 2). Inhibition of Ca 2ϩ channels can be voltage-dependent and is mediated by G protein ␤␥ subunits (1). In addition kinases, such as protein kinase C and tyrosine kinases, have been shown to inhibit Ca 2ϩ channels (2). As these multiple pathways converge in modulating Ca 2ϩ voltage-dependent channels, the question has arisen as to how these signals are integrated.Activation of tyrosine kinase by GABA B 1 receptors mediates voltage-independent inhibition of Ca v 2.2 (N-type) current in chick dorsal root ganglion (DRG) neurons (3), and the ␣ 1 subunit of the channel becomes tyrosine-phosphorylated (4). The tyrosine-phosphorylated channel binds to RGS12, a "regulator of G protein signaling" or RGS protein, that contains a phosphotyrosine binding domain (4). These findings raised the issue of whether tyrosine phosphorylation of the channel facilitates the recruitment of other signaling molecules that could then alter the functional characteristics of the channel and what role such interactions have in signal integration.We hypothesized that the Ca 2ϩ channel itself serves as an integrator by interacting with signaling molecules that regulate channel activity and by modulating downstream signals.To test this hypothesis, we have characterized interactions of the ␣ subunit of the Ca v 2.2 (N-type, ␣ 1B ) channel with signaling molecules, and we show how these interactions are regulated in an agonist and time-dependent manner and the consequences of such regulation on channel activity. Our results demonstrate that dynamic interactions at the level of the Ca 2ϩ channel can have shor...

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Section: Recruitment Of Members Of the Ras Signaling Pathway To The Cmentioning

confidence: 99%

N-type Ca2+ Channels as Scaffold Proteins in the Assembly of Signaling Molecules for GABAB Receptor Effects

Richman

Tombler

Lau

et al. 2004

Journal of Biological Chemistry

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“…Various substrates of CaMKII have been characterized in nerve terminals, and for some of them functional changes were shown to be regulated by phosphorylation (Greengard et al 1993;Yokoyama et al 1997;Risinger and Bennet 1999;Verona et al 2000). The finding that the basal level of presynaptic CaMKII autonomous activity in hippocampus is increased following DMI treatment is particularly intriguing.…”

Section: Dmi Treatment Increases Autonomous Activity Of Camkii In Synmentioning

confidence: 99%

Modifications in Brain CaM Kinase II after Long-Term Treatment with Desmethylimipramine

Consogno

2001

Neuropsychopharmacology

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“…4) as these kinases are known to influence the activity/trafficking of monoamine transporters as well as interactions of SYN1A with other presynaptic proteins including Munc18 and Ca 2+ channels (Fujita et al, 1996;Yokoyama et al, 1997). SYN1A is required for PMA-mediated inhibition of GAT1 GABA transporters in primary hippocampal neurons (Beckman et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Calcium-dependent interactions of the human norepinephrine transporter with syntaxin 1A

Sung

Blakely

2007

Molecular and Cellular Neuroscience

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The norepinephrine (NE) transporter (NET) terminates noradrenergic signaling by clearing released NE at synapses. The activity of NET can be rapidly regulated by depolarization and receptor activation via Ca 2+ and kinase/phosphatase linked pathways. The SNARE protein syntaxin 1A (SYN1A) interacts with NET and influences transporter surface trafficking and catalytic activity. In this study, we establish a link between changes in intracellular Ca 2+ and SYN1A/NET interactions. SYN1A influenced NE transport only in the presence of Ca 2+ in brain cortical synaptosomes. Although NET/SYN1A associations were sensitive to manipulations of Ca 2+ in CHO cells, in vitro binding experiments using purified NET and SYN1A fusion proteins demonstrated a lack of direct Ca 2+ sensitivity. Disruption of NET/SYN1A interaction abolished inhibition of NE transport by phorbol ester (PMA) to activate protein kinase C (PKC), but had no effect on transport inhibition by the Ca 2+ calmodulin kinase (CaMK) inhibitor KN93. Furthermore, PMA enhanced Ca 2+ dependent modulation of NE transport in synaptosomes. Our data reveal roles for SYN1A in the Ca 2+ -dependent regulation of NET, likely reliant on regulation by PKC signaling, but independent of CaMK.

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Phosphorylation of the Synaptic Protein Interaction Site on N-type Calcium Channels Inhibits Interactions with SNARE Proteins

Cited by 137 publications

References 57 publications

N-type Ca2+ Channels as Scaffold Proteins in the Assembly of Signaling Molecules for GABAB Receptor Effects

N-type Ca2+ Channels as Scaffold Proteins in the Assembly of Signaling Molecules for GABAB Receptor Effects

Modifications in Brain CaM Kinase II after Long-Term Treatment with Desmethylimipramine

Calcium-dependent interactions of the human norepinephrine transporter with syntaxin 1A

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