scholarly journals Role of L-Type Voltage-Gated Calcium Channels in Epileptiform Activity of Neurons

2021 ◽  
Vol 22 (19) ◽  
pp. 10342
Author(s):  
Denis P. Laryushkin ◽  
Sergei A. Maiorov ◽  
Valery P. Zinchenko ◽  
Sergei G. Gaidin ◽  
Artem M. Kosenkov
Keyword(s):  
Calcium Channels ◽  
Hippocampal Neurons ◽  
Epileptiform Activity ◽  
Gaba A ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Effective Doses ◽  
High Doses ◽  
Paroxysmal Depolarization Shift

Epileptic discharges manifest in individual neurons as abnormal membrane potential fluctuations called paroxysmal depolarization shift (PDS). PDSs can combine into clusters that are accompanied by synchronous oscillations of the intracellular Ca2+ concentration ([Ca2+]i) in neurons. Here, we investigate the contribution of L-type voltage-gated calcium channels (VGCC) to epileptiform activity induced in cultured hippocampal neurons by GABA(A)R antagonist, bicuculline. Using KCl-induced depolarization, we determined the optimal effective doses of the blockers. Dihydropyridines (nifedipine and isradipine) at concentrations ≤ 10 μM demonstrate greater selectivity than the blockers from other groups (phenylalkylamines and benzothiazepines). However, high doses of dihydropyridines evoke an irreversible increase in [Ca2+]i in neurons and astrocytes. In turn, verapamil and diltiazem selectively block L-type VGCC in the range of 1–10 μM, whereas high doses of these drugs block other types of VGCC. We show that L-type VGCC blockade decreases the half-width and amplitude of bicuculline-induced [Ca2+]i oscillations. We also observe a decrease in the number of PDSs in a cluster and cluster duration. However, the pattern of individual PDSs and the frequency of the cluster occurrence change insignificantly. Thus, our results demonstrate that L-type VGCC contributes to maintaining the required [Ca2+]i level during oscillations, which appears to determine the number of PDSs in the cluster.

scholarly journals The Paroxysmal Depolarization Shift: Reconsidering Its Role in Epilepsy, Epileptogenesis and Beyond

2019 ◽  
Vol 20 (3) ◽  
pp. 577 ◽  
Author(s):  
Helmut Kubista ◽  
Stefan Boehm ◽  
Matej Hotka
Keyword(s):  
Calcium Channels ◽  
Neuronal Membrane ◽  
Neuronal Dysfunction ◽  
Interictal Spikes ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Epilepsy Therapy ◽  
Novel Targets ◽  
Paroxysmal Depolarization Shift ◽  
First Time

Paroxysmal depolarization shifts (PDS) have been described by epileptologists for the first time several decades ago, but controversy still exists to date regarding their role in epilepsy. In addition to the initial view of a lack of such a role, seemingly opposing hypotheses on epileptogenic and anti-ictogenic effects of PDS have emerged. Hence, PDS may provide novel targets for epilepsy therapy. Evidence for the roles of PDS has often been obtained from investigations of the multi-unit correlate of PDS, an electrographic spike termed “interictal” because of its occurrence during seizure-free periods of epilepsy patients. Meanwhile, interictal spikes have been found to be associated with neuronal diseases other than epilepsy, e.g., Alzheimer’s disease, which may indicate a broader implication of PDS in neuropathologies. In this article, we give an introduction to PDS and review evidence that links PDS to pro- as well as anti-epileptic mechanisms, and to other types of neuronal dysfunction. The perturbation of neuronal membrane voltage and of intracellular Ca2+ that comes with PDS offers many conceivable pathomechanisms of neuronal dysfunction. Out of these, the operation of L-type voltage-gated calcium channels, which play a major role in coupling excitation to long-lasting neuronal changes, is addressed in detail.

scholarly journals Role of voltage-gated calcium channels in epilepsy

2009 ◽  
Vol 460 (2) ◽  
pp. 395-403 ◽  
Author(s):  
Gerald W. Zamponi ◽  
Philippe Lory ◽  
Edward Perez-Reyes
Keyword(s):  
Calcium Channels ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels

scholarly journals Proteolytic maturation of α2δ controls the probability of synaptic vesicular release

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Laurent Ferron ◽  
Ivan Kadurin ◽  
Annette C Dolphin
Keyword(s):  
Calcium Channels ◽  
Inhibitory Effect ◽  
Wild Type ◽  
Voltage Gated ◽  
Synaptic Release ◽  
Voltage Gated Calcium Channels ◽  
Vesicular Release ◽  
Active Zones ◽  
Asynchronous Release

Auxiliary α2δ subunits are important proteins for trafficking of voltage-gated calcium channels (CaV) at the active zones of synapses. We have previously shown that the post-translational proteolytic cleavage of α2δ is essential for their modulatory effects on the trafficking of N-type (CaV2.2) calcium channels (Kadurin et al., 2016). We extend these results here by showing that the probability of presynaptic vesicular release is reduced when an uncleaved α2δ is expressed in rat neurons and that this inhibitory effect is reversed when cleavage of α2δ is restored. We also show that asynchronous release is influenced by the maturation of α2δ−1, highlighting the role of CaV channels in this component of vesicular release. We present additional evidence that CaV2.2 co-immunoprecipitates preferentially with cleaved wild-type α2δ. Our data indicate that the proteolytic maturation increases the association of α2δ−1 with CaV channel complex and is essential for its function on synaptic release.

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