The role of Ca2+/calmodulin-dependent protein kinase II in mechanisms underlying neuronal hyperexcitability induced by repeated, brief exposure to hypoxia or high K+ in rat hippocampal slices

Yechikhov, Sergey; Shchipakina, T. G.; Savina, T. A.; Kalemenev, S. V.; Levin, S. G.; Godukhin, O. V.

doi:10.1016/s0304-3940(02)01154-0

Cited by 7 publications

(3 citation statements)

References 15 publications

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“…CaMKII can be neatly suited to support the activity of bursting neurons connected via glutamatergic synapses. Of note, CA1 pyramidal neurons acquire an epileptic (repetitive) activity after brief exposures to high K + or hypoxia (Yechikhov et al 2002) that is dependent on Ca L channels and CaMKII. Ca L channels in preBötC neurons are potentiated after brief episodes of hypoxia due to activation of metabotropic glutamate receptors (Mironov & Richter, 1998) but the effects perhaps should be revisited to examine possible involvement of CaMKII that facilitates Ca L channels in the heart (Wu et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Calmodulin and calmodulin kinase II mediate emergent bursting activity in the brainstem respiratory network (preBötzinger complex)

Mironov

2013

The Journal of Physiology

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Key points• Rhythmic network activity can be controlled by intracellular signalling pathways but their possible role is largely not yet elucidated.• This study is focused on the mechanisms of emergence and maintenance of synchronous rhythmic activity within the preBötzinger complex (preBötC), an essential part of the respiratory network in the brainstem.• Depression of the bursting activity by brief hypoxia and electrical stimulation correlated well with ADP-mediated inhibition of TRPM4 channels.• Long-lasting increases in calcium during the treatments stimulated calmodulin kinase that facilitated glutamatergic synapses and augmented rhythmic activity.• The results will help us better understand how respiratory rhythm is generated and how it is restored in various respiratory disorders Abstract Emergence of persistent activity in networks can be controlled by intracellular signalling pathways but the mechanisms involved and their role are not yet fully explored. Using calcium imaging and patch-clamp we examined the rhythmic activity in the preBötzinger complex (preBötC) in the lower brainstem that generates the respiratory motor output. In functionally intact acute slices brief hypoxia, electrical stimulation and activation of AMPA receptors transiently depressed bursting activity which then recovered with augmentation. The effects were abrogated after chelation of intracellular calcium, blockade of L-type calcium channels and inhibition of calmodulin (CaM) and CaM kinase (CaMKII). Rhythmic calcium transients and synaptic drive currents in preBötC neurons in the organotypic slices showed similar CaM-and CaMKII-dependent responses. The stimuli increased the amplitude of spontaneous and miniature excitatory synaptic currents indicating postsynaptic changes at glutamatergic synapses. In the acute and organotypic slices, CaM stimulated and ADP inhibited calcium-dependent TRPM4 channels and CaMKII augmented synaptic drive currents. Experimental data and simulations show the role of ADP and CaMKII in the control of bursting activity and its relation to intracellular signalling. I propose that CaMKII-mediated facilitation of glutamatergic transmission strengthens emergent synchronous activity within preBötC that is then maintained by periodic surges of calcium during the bursts. This may find implications in restoration and consolidation of autonomous activity in the respiratory disorders.

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Section: Discussionmentioning

confidence: 99%

Calmodulin and calmodulin kinase II mediate emergent bursting activity in the brainstem respiratory network (preBötzinger complex)

Mironov

2013

The Journal of Physiology

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“…To our knowledge, this is the first demonstration of L-VGCC enhancement by transient hypoxia in cortical neurons, which could contribute to post-hypoxic cortical hyperexcitability (Yechikhov et al, 2002), seizures or status epilepticus (Bladin et al, 2000; Krumholz et al, 1988). Increased intracellular Ca 2+ might activate calcium-dependent processes leading to necrotic or apoptotic cell death (Wasterlain et al, 1993), or alternatively, L-VGCC upregulation and calcium entry might facilitate post-hypoxic dephosphorylation and translocation of the Ca 2+ -dependent potassium channel Kv2.1, which suppresses neuronal excitability, and thus have a compensatory or protective effect (Misonou et al, 2005).…”

Section: Discussionmentioning

confidence: 84%

Hypoxia enhances high-voltage-activated calcium currents in rat primary cortical neurons via calcineurin

et al. 2012

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Hypoxia regulates neuronal ion channels, sometimes resulting in seizures. We evaluated the effects of brief sustained hypoxia (1% O2, 4 h) on voltage-gated calcium channels (VGCCs) in cultured rat primary cortical neurons. High-voltage activated (HVA) Ca2+ currents were acquired immediately after hypoxic exposure or after 48 h recovery in 95% air/5% CO2. Maximal Ca2+ current density increased 1.5-fold immediately after hypoxia, but reverted to baseline after 48 h normoxia. This enhancement was primarily due to an increase in L-type VGCC activity, since nimodipine-insensitive residual Ca2+ currents were unchanged. The half-maximal potentials of activation and steady-state inactivation were unchanged. The calcineurin inhibitors FK-506 (in the recording pipette) or cyclosporine A (during hypoxia) prevented the post-hypoxic increase in HVA Ca2+ currents, while rapamycin and okadaic acid did not. L-type VGCCs were the source of Ca2+ for calcineurin activation, as nimodipine during hypoxia prevented post-hypoxic enhancement. Hypoxia transiently potentiated L-type VGCC currents via calcineurin, suggesting a positive feedback loop to amplify neuronal calcium signaling that may contribute to seizure generation.

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“…In order to investigate the possible mechanism of Q808, other electrophysiological experiments were performed. In an epileptiform model in which seizures were induced by high-K + [ 21 , 22 ], a high concentration of exogenous K + ions disturbs the balance of K + inside and outside the cell membrane, which closes outwardly rectifying potassium ion channels, leading to depolarization and enhanced excitability. In this experiment, Q808 significantly reduced the frequency of neuronal action potentials, which suggests that it may be increasing the concentration of K + ions or inactivating K + channels.…”

Section: Discussionmentioning

confidence: 99%

Current Study of the Mechanism of Action of the Potential Anti-Epileptic Agent Q808

Zhang

Wang³

et al. 2017

Molecules

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Our previous study showed that the anticonvulsant Q808 might be effective against seizures induced by maximal electroshock, pentylenetetrazole (PTZ), isoniazid (ISO), thiosemicarbazide (THIO), and 3-mercaptopropionic acid (3-MP). In the present study, we explored the possible mechanism of action of Q808. Results obtained with high-performance liquid chromatography (HPLC) suggest that Q808 may affect neurotransmitter content in the brain, by specifically increasing GABA content in the rat hippocampus at doses of 40 mg/kg and 80 mg/kg, and by reducing the content of glutamate and glutamine in the rat thalamus at a dose of 80 mg/kg. Intriguingly, there were no changes in the neurotransmitter content in the cortex in response to Q808. In vitro brain slice electrophysiological studies showed that 10−5 M Q808 enhanced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in corn cells of the CA1 area of the hippocampus, and had no effect on the amplitude of sIPSCs, the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), or γ-aminobutyric acid (GABA) receptor-mediated currents in primary cultured hippocampal neurons. These findings suggest that the antiepileptic activity of Q808 may be due to its ability to increase the amount of GABA between synapses, without affecting the function of GABA receptors.

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The role of Ca2+/calmodulin-dependent protein kinase II in mechanisms underlying neuronal hyperexcitability induced by repeated, brief exposure to hypoxia or high K+ in rat hippocampal slices

Cited by 7 publications

References 15 publications

Calmodulin and calmodulin kinase II mediate emergent bursting activity in the brainstem respiratory network (preBötzinger complex)

Calmodulin and calmodulin kinase II mediate emergent bursting activity in the brainstem respiratory network (preBötzinger complex)

Hypoxia enhances high-voltage-activated calcium currents in rat primary cortical neurons via calcineurin

Current Study of the Mechanism of Action of the Potential Anti-Epileptic Agent Q808

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