Determinants of Metabotropic Glutamate Receptor-5-mediated Ca2+ and Inositol 1,4,5-Trisphosphate Oscillation Frequency

Nash, Mark S.; Schell, Michael J.; Atkinson, Peter J.; Johnston, Neil R.; Nahorski, Stefan R.; Challiss, R. A. John

doi:10.1074/jbc.m205622200

Cited by 102 publications

(180 citation statements)

References 59 publications

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“…Phenotypically these changes contrasted markedly with the oscillatory patterns of IP 3 production recorded in non-excitable cells (21)(22)(23)31). It seemed unlikely, therefore, that these involved either the dynamic uncoupling mechanism described for metabotropic glutamate-R5a receptor-induced IP 3 oscillations (22,31) or the smaller Ca 2ϩ -induced IP 3 oscillations observed for ␣ 1B -adrenergic receptors (23). However, because fluctuations in IP 3 concentration were only evident in hippocampal cultures challenged with mACh receptor agonist in the absence of TTx a synergy between action potential-induced synaptic activity and G q/11 -coupled GPCR activation was indicated.…”

Section: Initiation Of Ipmentioning

confidence: 91%

“…1C) in the presence of 0.5 M TTx to block synaptic activity. This resulted from increased IP 3 levels as opposed to PIP 2 depletion because metabolism of IP 3 by co-expression with a DsRed2-tagged IP 3 3-kinase A, but not the kinase-dead enzyme (22,24), inhibited GFP-PH PLC␦ translocation by Ͼ80% (Fig. 1, D and E, n ϭ 11, p Ͻ 0.001).…”

Section: Methodsmentioning

confidence: 99%

“…Images were captured using an oil immersion ϫ100 objective and ϫ4.5 optical zoom. Cellular IP 3 levels were indexed as the relative change in fluorescence within a cytoplasmic region of interest as described previously (22,23,26). Drugs were applied (unless otherwise stated) through the perfusion lines at a rate of approx.…”

Section: Methodsmentioning

confidence: 99%

“…This probe binds PIP 2 with high specificity and affinity (20) but translocates to the cytoplasm when IP 3 accumulates (and PIP 2 depletes) (16,(21)(22)(23). We have transfected this probe into cultures of rat hippocampal neurons and show a dramatic facilitation of IP 3 production, which promotes Ca 2ϩ store release.…”

Section: Intracellular Camentioning

confidence: 99%

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Synaptic Activity Augments Muscarinic Acetylcholine Receptor-stimulated Inositol 1,4,5-Trisphosphate Production to Facilitate Ca2+ Release in Hippocampal Neurons

Nash¹,

Willets

Billups

et al. 2004

Journal of Biological Chemistry

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Intracellular Ca2؉ store release contributes to activitydependent synaptic plasticity in the central nervous system by modulating the amplitude, propagation, and temporal dynamics of cytoplasmic Ca 2؉ changes. However, neuronal Ca 2؉ stores can be relatively insensitive to increases in the store-mobilizing messenger inositol 1,4,5-trisphosphate (IP 3 ). Using a fluorescent biosensor we have visualized M 1 muscarinic acetylcholine (mACh) receptor signaling in individual hippocampal neurons and observed increased IP 3 production in the absence of concurrent Ca 2؉ store release. However, coincident glutamate-mediated synaptic activity elicited enhanced and oscillatory IP 3 production that was dependent upon ongoing mACh receptor stimulation and S-␣-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid receptor activation of Ca 2؉ entry. Moreover, the enhanced levels of IP 3 now mobilized Ca 2؉ from intracellular stores that were refractory to the activation of mACh receptors alone. We conclude that convergent ionotropic and metabotropic receptor inputs can facilitate Ca 2؉ signaling by enhancing IP 3 production as well as augmenting release by Ca 2؉ -induced Ca 2؉ release.There is now substantial evidence that fundamental neuronal properties ranging from membrane excitability through gene expression to regulation of synaptic plasticity can be modulated by changes in intracellular free calcium (Ca 2ϩ i ) (1-4). In particular, it has been increasingly recognized that neuronal intracellular stores, far from just acting as a sink for Ca 2ϩ , can play a critical role in modulating the amplitude, localization, propagation, and temporal dynamics of neuronal Ca 2ϩ i transients (1-3, 5, 6). The key current questions relate to the mechanisms that might control local and global Ca 2ϩ signaling within the highly structured and functional domains of central neurons.A major player in Ca 2ϩ store release is the intracellular messenger IP 3 that can be generated by phospholipase C-mediated hydrolysis of the minor membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ) 1 (4). This signaling pathway is particularly prominent in the central nervous system, and a wide range of G protein-coupled receptors (GPCRs) can initiate the generation of IP 3 in neurons (1). Currently, models support a role for IP 3 receptors in the propagation of Ca 2ϩ waves observed in dendrites following activation of GPCRs such as muscarinic acetylcholine (mACh) and metabotropic glutamate receptors (2,7,8 (7, 9 -12). Alternatively or additionally, in view of the ability of Ca 2ϩ influx to activate PLC activity in neurons (13-16) enhanced production of IP 3 could further enhance regenerative Ca 2ϩ release (7,17). Indeed, the more favorable properties of IP 3 rather than Ca 2ϩ as a diffusible messenger (18) and the micro regional constraints imposed between the sites of generation and action of IP 3 in neurons such as hippocampal CA1 pyramidal cells (7) or sympathetic ganglia (19) would support such a model.In the present study we attempt to address these me...

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Section: Initiation Of Ipmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Intracellular Camentioning

confidence: 99%

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Synaptic Activity Augments Muscarinic Acetylcholine Receptor-stimulated Inositol 1,4,5-Trisphosphate Production to Facilitate Ca2+ Release in Hippocampal Neurons

Nash¹,

Willets

Billups

et al. 2004

Journal of Biological Chemistry

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“…These findings demonstrate that mGluR5 trafficking is regulated by S901 phosphorylation and CaM binding in both heterologous cells and in neurons. mGluR5 activation triggers Ca 2ϩ oscillations after agonist treatment, and the frequency of the Ca 2ϩ spikes is correlated with mGluR5 receptor density on the plasma membrane (8,22). Therefore, regulation of mGluR5 surface expression by S901 phosphorylation is likely to affect mGluR5-initiated signaling.…”

Section: Resultsmentioning

confidence: 99%

Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5

Lee

Choi

et al. 2008

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

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Metabotropic glutamate receptors (mGluRs) 1-8 are G proteincoupled receptors (GPCRs) that modulate excitatory neurotransmission, neurotransmitter release, and synaptic plasticity. PKC regulates many aspects of mGluR function, including protein-protein interactions, Ca 2؉ signaling, and receptor desensitization. However, the mechanisms by which PKC regulates mGluR function are poorly understood. We have now identified calmodulin (CaM) as a dynamic regulator of mGluR5 trafficking. We show that the major PKC phosphorylation site on the intracellular C terminus of mGluR5 is serine 901 (S901), and phosphorylation of this residue is up-regulated in response to both receptor and PKC activation. In addition, S901 phosphorylation inhibits mGluR5 binding to CaM, decreasing mGluR5 surface expression. Furthermore, blocking PKC phosphorylation of mGluR5 on S901 dramatically affects mGluR5 signaling by prolonging Ca 2؉ oscillations. Thus, our data demonstrate that mGluR5 activation triggers phosphorylation of S901, thereby directly linking PKC phosphorylation, CaM binding, receptor trafficking, and downstream signaling.phosphorylation ͉ protein kinase C ͉ receptor trafficking T he group I metabotropic glutamate receptor mGluR5 is highly expressed in the forebrain, where it regulates synaptic plasticity (1, 2). In addition, mGluR5 plays a role in pain (3) and addiction (4) and in neurological disorders such as fragile X syndrome (5, 6). Group I mGluRs are G protein-coupled receptors (GPCRs), which are coupled to phospholipase C, and receptor activation triggers phosphoinositide turnover, release of intracellular Ca 2ϩ , and activation of Protein Kinase C (PKC) (7). Although PKC activity regulates mGluR5-mediated Ca 2ϩ signaling and receptor function (8-11), there are no studies linking PKC phosphorylation of mGluR5 to receptor surface expression, endocytosis, or intracellular trafficking.Like other GPCRs, mGluR5 interacts with many proteins in addition to the guanine nucleotide-binding proteins (G proteins). Most of the binding sites for these protein-protein interactions reside within the long intracellular C-terminal domain of mGluR5, suggesting that this region is critical in the functional regulation of mGluR5. For example, the Homer proteins bind to the PPxxFR motif within the distal C terminus, the Tamalin protein associates with the distal C terminus, and calmodulin (CaM) and the E3 ligase Siah-1A bind to the first one-third of the mGluR5 C terminus (12-15). However, the dynamic regulation of these protein-protein interactions has not been described. CaM is a particularly intriguing candidate as an mGluR5 regulator because of its Ca 2ϩ dependence and its key role in synaptic plasticity (16,17). Furthermore, CaM binding to other GPCRs, including dopamine, opioid, and serotonin receptors, has been documented, consistent with a conserved regulatory role for CaM in regulating . We now show that PKC phosphorylation of serine 901 (S901) on mGluR5 inhibits CaM binding and decreases mGluR5 surface expression. Furthermore, preve...

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Astrocyte arborization enhances Ca²⁺ but not cAMP signaling plasticity

Pirnat

Božić

Dolanc

et al. 2021

Glia

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The plasticity of astrocytes is fundamental for their principal function, maintaining homeostasis of the central nervous system throughout life, and is associated with diverse exposomal challenges. Here, we used cultured astrocytes to investigate at subcellular level basic cell processes under controlled environmental conditions. We compared astroglial functional and signaling plasticity in standard serum-containing growth medium, a condition mimicking pathologic conditions, and in medium without serum, favoring the acquisition of arborized morphology. Using optoÀ/electrophysiologic techniques, we examined cell viability, expression of astroglial markers, vesicle dynamics, and cytosolic Ca 2+ and cAMP signaling. The results revealed altered vesicle dynamics in arborized astrocytes that was associated with increased resting [Ca 2 + ] i and increased subcellular heterogeneity in [Ca 2+ ] i , whereas [cAMP] i subcellular dynamics remained stable in both cultures, indicating that cAMP signaling is less prone to plastic remodeling than Ca 2+ signaling, possibly also in in vivo contexts. K E Y W O R D S astrocyte, Ca 2 + , cAMP, confocal microscopy, electrophysiology, vesicles 1 | INTRODUCTION Astrocytes are morphologically and functionally heterogeneous glial cells in the central nervous system. Immunolabeling of glial fibrillary acidic protein (GFAP) reveals major processes with finer cellular parts remaining unstained (Connor & Berkowitz, 1985) making astrocytes appear as stellate cells (Wolfes et al., 2017; Wolfes & Dean, 2018).Advanced visualization techniques revealed that astrocytes exhibit a more complex, spongioform structure (Benediktsson et al., 2005;Bushong et al., 2004). The morphological complexity of astrocytes arguably correlates with their extended homeostatic roles. Astroglia assist neuro-and synaptogenesis, provide substrates to neurons, regulate blood flow and the blood-brain barrier, control uptake and recycling of neurotransmitters, and produce and secrete various neurotrophic factors to regulate memory formation (Araque et al., 1999;

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Determinants of Metabotropic Glutamate Receptor-5-mediated Ca2+ and Inositol 1,4,5-Trisphosphate Oscillation Frequency

Cited by 102 publications

References 59 publications

Synaptic Activity Augments Muscarinic Acetylcholine Receptor-stimulated Inositol 1,4,5-Trisphosphate Production to Facilitate Ca2+ Release in Hippocampal Neurons

Synaptic Activity Augments Muscarinic Acetylcholine Receptor-stimulated Inositol 1,4,5-Trisphosphate Production to Facilitate Ca2+ Release in Hippocampal Neurons

Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5

Astrocyte arborization enhances Ca²⁺ but not cAMP signaling plasticity

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Determinants of Metabotropic Glutamate Receptor-5-mediated Ca2+ and Inositol 1,4,5-Trisphosphate Oscillation Frequency

Cited by 102 publications

References 59 publications

Synaptic Activity Augments Muscarinic Acetylcholine Receptor-stimulated Inositol 1,4,5-Trisphosphate Production to Facilitate Ca2+ Release in Hippocampal Neurons

Synaptic Activity Augments Muscarinic Acetylcholine Receptor-stimulated Inositol 1,4,5-Trisphosphate Production to Facilitate Ca2+ Release in Hippocampal Neurons

Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5

Astrocyte arborization enhances Ca2+ but not cAMP signaling plasticity

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Product

Resources

About

Astrocyte arborization enhances Ca²⁺ but not cAMP signaling plasticity