The role of serine/threonine protein phosphatases in exocytosis

Sim, Alistair T.R.; Baldwin, Monique L.; Rostas, John A. P.; Holst, Jeff; Ludowyke, Russell I.

doi:10.1042/bj20030484

Cited by 54 publications

(40 citation statements)

References 275 publications

(355 reference statements)

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“…As several protein kinases strongly affect vesicular DA release, phosphatases could have profound effects on DA exocytosis as well [141,164]. Though the actions of phosphatases are less well characterized, present evidence supports the notion that exocytosis is tuned by the balance between phosphorylation and dephosphorylation, with increased phosphorylation enhancing exocytosis.…”

Section: Inhibition Of Casupporting

confidence: 73%

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Targeting Exocytosis: Ins and Outs of the Modulation of Quantal Dopamine Release

Westerink

2006

CNSNDDT

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Dopaminergic neurotransmission is mediated by the vesicular release of dopamine (DA), i.e. DA exocytosis. DA exocytosis and its modulation are generally believed to affect neuronal communication, development, maintenance and survival, and contribute to extracellular DA levels in the brain. As a result, DA exocytosis likely plays an important role in several neurological and psychiatric disorders, like Parkinson's disease (PD) and schizophrenia. As exocytosis is part of a sophisticated ensemble of processes, it can be modulated at different levels, including DA synthesis, uptake and vesicular transport as well as Ca 2+ -homeostasis and exocytotic proteins. Nonetheless, to be effective, modulation of exocytosis should result in functional changes, which are reflected by changes in release frequency, vesicle contents, and the time course of the exocytotic event. As will be shown in this review, functional changes in DA exocytosis can be produced by e.g. pharmacological/drug treatment, feedback mechanisms and up/down-regulation of exocytosis-related proteins. Moreover, the mode of DA exocytosis, i.e. classical full fusion or kiss-and-run exocytosis, could also serve as a potential target for functional modulation of dopaminergic neurotransmission. Since the onset and progression of neurological and psychiatric disorders often show a strong correlation with changes in brain DA levels, DA synthesis, transport or uptake, the findings described in this review highlight the importance of the modulation of (the mode of) DA exocytosis for normal progression of dopaminergic neurotransmission and the potential of exocytotic processes as drug targets.

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Section: Inhibition Of Casupporting

confidence: 73%

“…the final fusion event [140]. Consequently, protein phosphatases play a key role in neurotransmission as well, since they can counteract the protein kinase-induced phosphorylation and change the basal levels of phosphorylation, which can result in profound effects [141].…”

Section: Modulation Of the Molecular Release Machinery By Phosphorylamentioning

confidence: 99%

Targeting Exocytosis: Ins and Outs of the Modulation of Quantal Dopamine Release

Westerink

2006

CNSNDDT

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“…Kinases play important, well documented, roles in the regulation of numerous cellular functions [10,43,67]. The physiological significance of serine/threonine protein phosphatases has also been appreciated, and these enzymes have been implicated in the regulation of ion channels, synaptic plasticity, exocytosis, and apoptosis [31,36,58,70].…”

Section: Introductionmentioning

confidence: 99%

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

Rosenberg

2007

Brain Research

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We have previously demonstrated that NMDA receptor-mediated extracellular adenosine accumulation in neuronal cultures is receptor-mediated and requires calcium influx. Because protein kinase C (PKC) is a calcium-dependent enzyme, we hypothesized that activation of PKC might be involved in NMDA-mediated adenosine accumulation. PKC inhibitors however, did not block NMDA-evoked adenosine accumulation, but rather, stimulated basal adenosine accumulation. These data suggested the possibility that NMDA receptor mediated adenosine accumulation involves net dephosphorylation rather than phosphorylation of one or more substrates. Thus, inhibition of kinases would be expected to increase adenosine accumulation and inhibition of phosphatases would be expected to block adenosine accumulation. To test this hypothesis, we used the phosphatase 1/2A inhibitors calyculin A and okadaic acid. Both inhibitors significantly reduced NMDA-evoked adenosine accumulation. In contrast phosphatase 2B inhibitors did not block NMDA-evoked adenosine accumulation. These data suggest that NMDAevoked adenosine accumulation is mediated by activation of phosphatase 1/2A. We have established previously that NMDA-mediated adenosine accumulation is associated with adenosine kinase inhibition. However, adenosine kinase is not a direct substrate for phosphatase 1/2A because inhibition of phosphatase 1/2A did not abolish NMDA-evoked adenosine kinase inhibition. Okadaic acid also had no effect on NO donor-evoked adenosine accumulation, which previously has been shown to be associated with adenosine kinase inhibition. Dephosphorylation of one or more proteins other than adenosine kinase as a consequence of NMDA receptor activation might play an important role in extracellular adenosine regulation, with important consequences for the regulation of excitatory synaptic transmission, plasticity, epileptogenesis, and excitotoxicity.

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“…One clone, pulled out by both the N-and P/Q-type Ca 2ϩ channel C termini (NCF and PCF), encoded a partial sequence of PP2c␣, a member of PP2c family (Price and Mumby, 1999;Herzig and Neumann, 2000;Sim et al, 2003). Of the 200 plus clones we have sequenced, PP2c␣ is the only phosphatase identified during screening (our unpublished data).…”

Section: Formation Of a Pp2c␣-camentioning

confidence: 99%

A Protein Phosphatase 2cα-Ca²⁺Channel Complex for Dephosphorylation of Neuronal Ca²⁺Channels Phosphorylated by Protein Kinase C

Wang²,

Lai³

et al. 2005

J. Neurosci.

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Phosphorylation and dephosphorylation are primary means for rapid regulation of a variety of neuronal functions, such as membrane excitability, neurotransmitter release, and gene expression. Voltage-gated Ca 2ϩ channels are targets for phosphorylation by a variety of second messengers through activation of different types of protein kinases (PKs). Protein phosphatases (PPs), like PKs, are equally important in regulating Ca 2ϩ channels in neurons. However, much less is understood about whether and how a particular type of PP contributes to regulating neuronal Ca 2ϩ channel activities. This is primarily because of the lack of specific inhibitors/activators for different types of PPs, particularly the PP2c family. The functional roles of PP2c and its substrates in the brain remain virtually unknown. During our yeast two-hybrid screening, PP2c␣ was pulled out by both N-and P/Q-type Ca 2ϩ channel C termini. This raised the possibility that PP2c␣ might be associated with voltage-gated Ca 2ϩ channels for regulation of the Ca 2ϩ channel activity. Biochemical studies show that PP2c␣ binds directly to neuronal Ca 2ϩ channels forming a functional protein complex in vivo. PP2c␣, unlike PP1, PP2a and PP2b, is more effective in dephosphorylation of neuronal Ca 2ϩ channels after their phosphorylation by PKC. In hippocampal neurons, disruption of the PP2c␣-Ca 2ϩ channel interaction significantly enhances the response of Ca 2ϩ channels to modulation by PKC. Thus, the PP2c␣-Ca 2ϩ channel complex is responsible for rapid dephosphorylation of Ca 2ϩ channels and may contribute to regulation of synaptic transmission in neurons.

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The role of serine/threonine protein phosphatases in exocytosis

Cited by 54 publications

References 275 publications

Targeting Exocytosis: Ins and Outs of the Modulation of Quantal Dopamine Release

Targeting Exocytosis: Ins and Outs of the Modulation of Quantal Dopamine Release

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

A Protein Phosphatase 2cα-Ca²⁺Channel Complex for Dephosphorylation of Neuronal Ca²⁺Channels Phosphorylated by Protein Kinase C

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The role of serine/threonine protein phosphatases in exocytosis

Cited by 54 publications

References 275 publications

Targeting Exocytosis: Ins and Outs of the Modulation of Quantal Dopamine Release

Targeting Exocytosis: Ins and Outs of the Modulation of Quantal Dopamine Release

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

A Protein Phosphatase 2cα-Ca2+Channel Complex for Dephosphorylation of Neuronal Ca2+Channels Phosphorylated by Protein Kinase C

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A Protein Phosphatase 2cα-Ca²⁺Channel Complex for Dephosphorylation of Neuronal Ca²⁺Channels Phosphorylated by Protein Kinase C