Protein kinase C involvement in the resting and interferon-?-induced K+ channel profile of microglial cells

Visentin, Sergio; Levi, Giulio

doi:10.1002/(sici)1097-4547(19970201)47:3<233::aid-jnr1>3.0.co;2-j

Cited by 18 publications

(6 citation statements)

References 26 publications

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“…On the basis of these observations, some of the pro-inflammatory substances produced by invading and/or endogenous inflammatory cells in the brain may preclude or diminish the microglia-deactivating properties of PGE 2 by limiting, via PKC, the EP2 receptormediated responses to the PG. This hypothesis is supported by the abundant literature providing evidence for the involvement of PKC in the transduction of the cellular effects of LPS and several cytokines (Fujihara et al, 1994;Jun et al, 1994;Sands et al, 1994;Shapira et al, 1994;Ballestas and Benveniste, 1995;McMillian et al, 1997;Visentin and Levi, 1997) but is difficult to prove experimentally, as these substances have pleiotropic effects and can, in some cases (Patrizio et al, 1995), interfere with other steps in the cAMP cascade.…”

Section: Discussionmentioning

confidence: 94%

Protein Kinase C Activation Reduces Microglial Cyclic AMP Response to Prostaglandin E₂ by Interfering with EP2 Receptors

Patrizio

Colucci

Levi

2000

Journal of Neurochemistry

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Abstract:We studied the modulation by protein kinase C (PKC) of the cyclic AMP (cAMP) accumulation induced by prostaglandin (PG) E 2 in rat neonatal microglial cultures. Short pretreatment of microglia with phorbol 12-myristate 13-acetate (PMA) or 4␤-phorbol 12,13-didecanoate, which activate PKC, but not with the inactive 4␣-phorbol 12,13-didecanoate, substantially reduced cAMP accumulation induced by 1 M PGE 2 . The action of PMA was dose and time dependent, and the maximal inhibition (ϳ85%) was obtained after 10-min preincubation with 100 nM PMA. The inhibitory effect of PMA was mimicked by diacylglycerol and was prevented by the PKC inhibitor calphostin C. As PMA did not affect isoproterenol-or forskolin-stimulated cAMP accumulation, we investigated whether activation of PKC decreased cAMP production by acting directly at PGE 2 EP receptors. Neither sulprostone (10 Ϫ9 -10 Ϫ5 M), a potent agonist at EP3 receptors (coupled to adenylyl cyclase inhibition), nor 17-phenyl-PGE 2 (10 Ϫ6 -10 Ϫ5 M), an agonist of EP1 receptors, modified cAMP accumulation induced by forskolin. On the contrary, 11-deoxy-16,16-dimethyl PGE 2 , which does not discriminate between EP2 and EP4 receptors, both coupled to the activation of adenylyl cyclase, and butaprost, a selective EP2 agonist, induced a dose-dependent elevation of cAMP that was largely reduced by PMA pretreatment, as in the case of PGE 2 . These results indicated EP2 receptors as a possible target of PKC and suggest that PKC-activating agents present in the pathological brain may prevent the cAMP-mediated microgliadeactivating function of PGE 2 .

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Section: Discussionmentioning

confidence: 94%

Protein Kinase C Activation Reduces Microglial Cyclic AMP Response to Prostaglandin E₂ by Interfering with EP2 Receptors

Patrizio

Colucci

Levi

2000

Journal of Neurochemistry

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“…Although no similar studies have been reported, some specific aspects of the current work can be compared with previous studies. Most studies of cultured microglia describe a K ϩ current that is essentially identical to Kv1.3 in its voltage and time dependence and block by 4-aminopyridine, charybdotoxin, margatoxin, and agitoxin-2 (Norenberg et al, 1994;Schlichter et al, 1996;Visentin and Levi, 1997;Eder, 1998;Schlichter and Khanna, 2002); however, discrepancies exist concerning changes in K ϩ channel expression under various conditions. There is some evidence that the Kv current in microglia can be increased by proinflammatory stimuli (e.g., LPS, interferon-␥), but large currents have also been Table 2, ChTx (50 nM) blocks 78% of Kv1.2, 95% of Kv1.3, and 96% of SK4 channels; AgTx (5 nM) blocks ϳ100% of Kv1.3 and Kv1.6 channels; ␣-DTx (50 nM) blocks 75% of Kv1.2 and 71% of Kv1.6 channels.…”

Section: Discussionmentioning

confidence: 99%

Microglia Kv1.3 Channels Contribute to Their Ability to Kill Neurons

Fordyce¹,

Jagasia²,

Zhu³

et al. 2005

J. Neurosci.

187

189

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Many CNS disorders involve an inflammatory response that is orchestrated by cells of the innate immune system: macrophages, neutrophils, and microglia (the endogenous CNS immune cell). Hence, there is considerable interest in anti-inflammatory strategies that target these cells. Microglia express Kv1.3 (KCNA3) channels, which we showed previously are important for their proliferation and the NADPH-mediated respiratory burst. Here, we demonstrate the potential for targeting Kv1.3 channels to control CNS inflammation. Rat microglia express Kv1.2, Kv1.3, and Kv1.5 transcripts and protein, but only a Kv1.3 current was detected. When microglia were activated with lipopolysaccharide or a phorbol ester, only the Kv1.3 transcript (but not protein) expression changed. Using a Transwell cell-culture system that allows separate drug treatment of microglia or neurons, we found that activated microglia killed postnatal hippocampal neurons through a process that requires Kv1.3 channel activity in microglia but not in neurons. A major neurotoxic molecule in this model was peroxynitrite, which is formed from superoxide and nitric oxide; thus, it is significant that Kv1.3 channel blockers reduced the respiratory burst, but not nitric oxide production, by the activated microglia. In addressing the biochemical pathway affected by Kv1.3 channel activity, we found that Kv1.3 acts via a different cellular mechanism from the broad-spectrum drug minocycline, which is often used in animal models of neuroinflammation. That is, the dose-dependent reduction in neuron killing by minocycline corresponded with a reduction in p38 mitogen-activated protein kinase activation in microglia; however, none of the Kv1.3 blockers affected p38 activation.

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“…P2X 7 receptor is an ATP-gated ion channel highly expressed in immune cells, particularly macrophages (Steinberg et al, 1987) mast cells (Cockcroft and Gomperts, 1979), and microglia (Visentin and Levi, 1997) where it controls the release of inflammatory cytokines, such as IL-1β and IL-18 (Ferrari et al, 2006). Activation of P2X 7 receptor induces efficient assembly of inflammosome, the protein complex which activates the IL-1β processing enzyme caspase-1.…”

Section: Blebbing and MV Formation Induced By P2x7 Receptor Activationmentioning

confidence: 99%

Microglial microvesicle secretion and intercellular signaling

Furlan²,

et al. 2012

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Microvesicles (MVs) are released from almost all cell brain types into the microenvironment and are emerging as a novel way of cell-to-cell communication. This review focuses on MVs discharged by microglial cells, the brain resident myeloid cells, which comprise ∼10–12% of brain population. We summarize first evidence indicating that MV shedding is a process activated by the ATP receptor P2X7 and that shed MVs represent a secretory pathway for the inflammatory cytokine IL-β. We then discuss subsequent findings which clarify how IL-1 β can be locally processed and released from MVs into the extracellular environment. In addition, we describe the current understanding about the mechanism of P2X7-dependent MV formation and membrane abscission, which, by involving sphingomyelinase activity and ceramide formation, may share similarities with exosome biogenesis. Finally we report our recent results which show that microglia-derived MVs can stimulate neuronal activity and participate to the propagation of inflammatory signals, and suggest new areas for future investigation.

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Protein kinase C involvement in the resting and interferon-?-induced K+ channel profile of microglial cells

Cited by 18 publications

References 26 publications

Protein Kinase C Activation Reduces Microglial Cyclic AMP Response to Prostaglandin E₂ by Interfering with EP2 Receptors

Protein Kinase C Activation Reduces Microglial Cyclic AMP Response to Prostaglandin E₂ by Interfering with EP2 Receptors

Microglia Kv1.3 Channels Contribute to Their Ability to Kill Neurons

Microglial microvesicle secretion and intercellular signaling

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Protein kinase C involvement in the resting and interferon-?-induced K+ channel profile of microglial cells

Cited by 18 publications

References 26 publications

Protein Kinase C Activation Reduces Microglial Cyclic AMP Response to Prostaglandin E2 by Interfering with EP2 Receptors

Protein Kinase C Activation Reduces Microglial Cyclic AMP Response to Prostaglandin E2 by Interfering with EP2 Receptors

Microglia Kv1.3 Channels Contribute to Their Ability to Kill Neurons

Microglial microvesicle secretion and intercellular signaling

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Protein Kinase C Activation Reduces Microglial Cyclic AMP Response to Prostaglandin E₂ by Interfering with EP2 Receptors

Protein Kinase C Activation Reduces Microglial Cyclic AMP Response to Prostaglandin E₂ by Interfering with EP2 Receptors