The Metabotropic Glutamate Receptor mGluR5 Induces Calcium Oscillations in Cultured Astrocytes via Protein Kinase C Phosphorylation

Nakahara, Kiyoshi; Okada, Masamichi; Nakanishi, Shigetada

doi:10.1046/j.1471-4159.1997.69041467.x

Cited by 133 publications

(107 citation statements)

References 36 publications

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“…Similar to the observations in mGluR5a-expressed HEK-293 cells (9), the PKC activator abolishes Ca 2ϩ response in cultured astrocytes (21,23). Moreover, both PKC inhibitor and PP1/PP2A phosphatase inhibitor convert Ca 2ϩ response from an oscillatory to non-oscillatory pattern, suggesting that the same mechanism underlies the generation of [Ca 2ϩ ] i oscillations in mGluR5-expressed heterologous and native cells (21). Thus, it may also occur in native cells that oscillatory/non-oscillatory mobilizations of Ca 2ϩ result in distinct coupling mechanisms during prolonged stimulation of mGluRs.…”

Section: Casupporting

confidence: 80%

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Diversity of Calcium Signaling by Metabotropic Glutamate Receptors

Kawabata¹,

Kohara²,

Tsutsumi³

et al. 1998

Journal of Biological Chemistry

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(840) of mGluR5a by PKC interferes with the signal transduction through mGluR5a. We hypothesized that repetitive phosphorylation and dephosphorylation of mGluR5a could induce [Ca2ϩ] i oscillations by signaling on and off. In mGluR1␣, nonphosphorylation at aspartate (854) produces a non-oscillatory and PKC activator-resistant Ca 2ϩ response (9). This previous study provides the first evidence that an agonist can produce oscillatory/non-oscillatory patterns of Ca 2ϩ response by stimulating different receptor subtypes. However, it remained uncertain whether and how these two mGluRs control different cellular processes depending on their oscillatory/non-oscillatory Ca 2ϩ responses. We report here that prolonged stimulation of mGluR1␣ induced an increase in [Ca2ϩ] i that consisted of an initial transient peak and a subsequent steady plateau or an oscillatory increase in [Ca 2ϩ ] i . The transient phase was largely attributed to Ca 2ϩ release from intracellular Ca 2ϩ stores, but the sustained phase was solely due to Ca 2ϩ influx through a mGluR1␣ receptor-operated Ca 2ϩ channel. On the other hand, prolonged stimulation of mGluR5a continuously induced [Ca 2ϩ ] i oscillations through mobilization of Ca 2ϩ from the intracellular Ca 2ϩ stores. The coupling mechanism in the sustained phase of Ca 2ϩ response is determined by oscillatory/non-oscillatory patterns of the initial Ca 2ϩ response but not by the receptor identity. Thus, during prolonged stimulation of mGluRs, oscillatory/nonoscillatory patterns of Ca 2ϩ response lead to different coupling mechanisms in Ca 2ϩ signaling. MATERIALS AND METHODSFura-2 acetoxymethyl ester (Fura-2/AM) and phorbol-12-myristate-13-acetate (PMA) were from Wako Pure Chemical Industries. SK&F96365 and nimodipine were from Funakoshi. The mGluR1␣ antagonist, 1a-(N-phenyl)carbamoyl-1a,7a-dihydro-7(1H)-hydroxyiminocyclopropa[b]chromen (10) was synthesized in our laboratory.For construction of the mutant receptors, mGluR1␣(T) and mGluR5a(D), aspartate (854) of mGluR1␣ and threonine (840) of mGluR5a were changed into threonine and aspartate, respectively, as described previously (9). The cDNA encoding rat mGluR1␣, mGluR5a,

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Section: Casupporting

confidence: 80%

“…In cultured astrocytes, glutamate induces [Ca 2ϩ ] i oscillations through mGluR5 (21,22). Similar to the observations in mGluR5a-expressed HEK-293 cells (9), the PKC activator abolishes Ca 2ϩ response in cultured astrocytes (21,23).…”

Section: Casupporting

confidence: 74%

Diversity of Calcium Signaling by Metabotropic Glutamate Receptors

Kawabata¹,

Kohara²,

Tsutsumi³

et al. 1998

Journal of Biological Chemistry

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“…This process may involve the release of calcium from intracellular stores and the generation of intercellular calcium waves, as shown in cultured astrocytes challenged with glutamate. [33][34][35] This 'synchronizing' activity of mGlu5 receptors might contribute to explain the heterogenous response of NPC cultures to MPEP or high concentrations of LY341495, as revealed by a distribution pattern of neurosphere diameters with multiple peaks (see Figure 5). Activation of mGlu5 receptors could also support NPC proliferation by stimulating the MAPK pathway, similarly to that observed for muscarinic 36,37 or opioid 38 receptor activation.…”

Section: Discussionmentioning

confidence: 98%

Endogenous activation of metabotropic glutamate receptors supports the proliferation and survival of neural progenitor cells

et al. 2005

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The use of neural progenitor cells (NPCs) is limited by the incomplete knowledge of the extracellular signals regulating their proliferation and survival. We report that cultured mouse NPCs express functional mGlu3 and mGlu5 metabotropic glutamate receptors. Pharmacological blockade of both receptors reduced NPC proliferation and survival, whereas activation of mGlu5 receptors substantially enhanced cell proliferation. Adult mice lacking mGlu5 receptors or treated with mGlu5 or mGlu3 receptor antagonists showed a dramatic reduction in the number of dividing neuroprogenitors present in the subventricular zone and in the dentate gyrus of the hippocampus. These data disclose a novel function of mGlu receptors and offer new potential strategies for the optimization of cell replacement therapy in neurodegenerative disorders.

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“…Thermally inactivated toxin did not display this inhibitory activity (n ϭ 4; not shown). Furthermore, BoNT A also blocked Ϸ30% of the 2.5-fold potentiation of TRPV1 activity evoked by the activation of metabotropic GluR5, a phospholipase C-coupled receptor that activates PKC (38,39) (Fig. 6).…”

Section: Fig 6 Potentiation Of Trpv1 Activity By Mglur5 Activationmentioning

confidence: 87%

Regulated Exocytosis Contributes to Protein Kinase C Potentiation of Vanilloid Receptor Activity

Morenilla‐Palao

Planells-Cases

García-Sanz

et al. 2004

Journal of Biological Chemistry

392

302

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The vanilloid receptor-1 (TRPV1) plays a key role in the perception of peripheral thermal and inflammatory pain. TRPV1 expression and channel activity are notably up-regulated by proalgesic agents. The transduction pathways involved in TRPV1 sensitization are still elusive. We have used a yeast two-hybrid screen to identify proteins that associate with the N terminus of TRPV1. We report that two vesicular proteins, Snapin and synaptotagmin IX (Syt IX), strongly interact in vitro and in vivo with the TRPV1 N-terminal domain. In primary dorsal root ganglion neurons, TRPV1 co-distributes in vesicles with Syt IX and the vesicular protein synaptobrevin. Neither Snapin nor Syt IX affected channel function, but they notably inhibited protein kinase C (PKC)-induced potentiation of TRPV1 channel activity with a potency that rivaled the blockade evoked by botulinum neurotoxin A, a potent blocker of neuronal exocytosis. Noteworthily, we found that PKC activation induced a rapid delivery of functional TRPV1 channels to the plasma membrane. Botulinum neurotoxin A blocked the TRPV1 membrane translocation induced by PKC that was activated with a phorbol ester or the metabotropic glutamate receptor mGluR5. Therefore, our results indicate that PKC signaling promotes at least in part the SNARE-dependent exocytosis of TRPV1 to the cell surface. Taken together, these findings imply that activitydependent delivery of channels to the neuronal surface may contribute to the buildup and maintenance of thermal inflammatory hyperalgesia in peripheral nociceptor terminals.TRPV1 1 is a capsaicin-, proton-and heat-sensitive, cationselective ion channel expressed in nociceptors that participates in the transduction of noxious chemical and thermal stimuli by sensory nerve endings in peripheral tissues (1-3). Heterologous expression of TRPV1 cDNA results in ionic currents that recapitulate most of the functional properties displayed by native capsaicin-and heat-activated currents in sensory neurons (1, 2). For instance, TRPV1 exhibits a time-and Ca 2ϩ -dependent desensitization, a long lasting refractory state during which the receptor does not respond to vanilloids or other stimuli (2). In addition, the channel activity of TRPV1 is remarkably upregulated by inflammatory mediators through the activation of phospholipase C and protein kinases A and C (PKA and PKC) signaling pathways (4 -13). Recent evidence shows that an increase in TRPV1 expression in peripheral nociceptors is critical for the maintenance of inflammatory hyperalgesia (14, 15). The involvement of TRPV1 in heat hypersensitivity is further underscored by the reduced sensitivity of mice lacking TRPV1 (16, 17) and by mice treated with receptor-specific antagonists (18).TRPV1 belongs to the family of transient receptor potential channels, which structurally resembles the family of voltagegated potassium or cyclic nucleotide-gated channels (19). Accordingly, these channels are presumed to be tetrameric assemblies of identical subunits (Fig. 1A), although heteromeric assemblies have be...

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The Metabotropic Glutamate Receptor mGluR5 Induces Calcium Oscillations in Cultured Astrocytes via Protein Kinase C Phosphorylation

Cited by 133 publications

References 36 publications

Diversity of Calcium Signaling by Metabotropic Glutamate Receptors

Diversity of Calcium Signaling by Metabotropic Glutamate Receptors

Endogenous activation of metabotropic glutamate receptors supports the proliferation and survival of neural progenitor cells

Regulated Exocytosis Contributes to Protein Kinase C Potentiation of Vanilloid Receptor Activity

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