Changes in the mRNAs encoding voltage-gated sodium channel types II and III in human epileptic hippocampus

Whitaker, William R. J.; Faull, Richard L.M.; Dragunow, Michael; Mee, Edward; Emson, Piers C.; Clare, Jeffrey J.

doi:10.1016/s0306-4522(01)00212-3

Cited by 71 publications

(40 citation statements)

References 54 publications

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“…However, both hypoinhibition and hyperexcitation can contribute to eplileptogensis. In the current work, Kaphzan et al (2013) demonstrate an ␣1-NaKA-dependent increase in Na v 1.6 at the AIS of hippocampal pyramidal cells of AS mice, consistent with proexcitatory changes observed in sodium channels in both epileptic patients (Whitaker et al 2001) and animal models of epilepsy (Blumenfeld et al 2009). Indeed, elevation of Na v 1.6 has been demonstrated in several epilepsy models (Blumenfeld et al 2009;Hargus et al 2013), suggesting an additional mechanism by which seizures may develop in AS mice.…”

supporting

confidence: 85%

Sodium-potassium ATPase emerges as a player in hippocampal phenotypes of Angelman syndrome mice

Hallengren

Vaden

2014

Journal of Neurophysiology

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supporting

confidence: 85%

Sodium-potassium ATPase emerges as a player in hippocampal phenotypes of Angelman syndrome mice

Hallengren

Vaden

2014

Journal of Neurophysiology

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“…Studies have suggested that alteration of the slow inactivated state, through interactions with S6 regions of VGSCs, could be clinically relevant in limiting the activity of neurons with abnormal activity. Both increases and decreases in levels of CNS enriched Nav1.2, -1.3, and -1.6 (as well as cardiac Nav1.5) isoforms have been reported following experimental seizures in animals and in human chronic epilepsy (21)(22)(23). Thus, changes in expression levels of lacosamide target proteins may have disease-modifying effects.…”

Section: The Anti-epileptic Drug (R)-lacosamide ((2r)-2-(acetylamino)mentioning

confidence: 99%

In Silico Docking and Electrophysiological Characterization of Lacosamide Binding Sites on Collapsin Response Mediator Protein-2 Identifies a Pocket Important in Modulating Sodium Channel Slow Inactivation

Wang

Brittain

Jarecki

et al. 2010

Journal of Biological Chemistry

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The anti-epileptic drug (R)-lacosamide ((2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide (LCM)) modulates voltage-gated sodium channels (VGSCs) by preferentially interacting with slow inactivated sodium channels, but the observation that LCM binds to collapsin response mediator protein 2 (CRMP-2) suggests additional mechanisms of action for LCM. We postulated that CRMP-2 levels affects the actions of LCM on VGSCs. CRMP-2 labeling by LCM analogs was competitively displaced by excess LCM in rat brain lysates. Manipulation of CRMP-2 levels in the neuronal model system CAD cells affected slow inactivation of VGSCs without any effects on other voltage-dependent properties. In silico docking was performed to identify putative binding sites in CRMP-2 that may modulate the effects of LCM on VGSCs. These studies identified five cavities in CRMP-2 that can accommodate LCM. CRMP-2 alanine mutants of key residues within these cavities were functionally similar to wildtype CRMP-2 as assessed by similar levels of enhancement in dendritic complexity of cortical neurons. Next, we examined the effects of expression of wild-type and mutant CRMP-2 constructs on voltage-sensitive properties of VGSCs in CAD cells: 1) steady-state voltage-dependent activation and fastinactivation properties were not affected by LCM, 2) CRMP-2 single alanine mutants reduced the LCM-mediated effects on the ability of endogenous Na ؉ channels to transition to a slow inactivated state, and 3) a quintuplicate CRMP-2 alanine mutant further decreased this slow inactivated fraction. Collectively, these results identify key CRMP-2 residues that can coordinate LCM binding thus making it more effective on its primary clinical target.

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“…Various animal models of temporal lobe epilepsy (TLE) are associated both with changes in the levels of messenger RNAs (mRNAs) for different sodium channel subtypes (2)(3)(4) and with modulation of sodium current behavior (5,6). Alterations in sodium channel mRNA also have been described in tissue samples from human TLE patients (7,8). These studies have focused on the hippocampus; however, none has specifically investigated sodium channel behavior in the entorhinal cortex (EC), which forms the principal interface between the hippocampus and neocortex and has been implicated in the genesis of ictal activity associated with TLE (9).…”

mentioning

confidence: 99%

Increased Persistent Sodium Currents in Rat Entorhinal Cortex Layer V Neurons in a Post–Status Epilepticus Model of Temporal Lobe Epilepsy

2003

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Summary:Purpose: Spontaneous seizures in rats emerge several weeks after induction of status epilepticus with pharmacologic treatment or electrical stimulation, providing an animal model for human temporal lobe epilepsy. In this study, we investigated whether status epilepticus caused changes in the function of voltage-gated sodium channels in entorhinal cortex layer V neurons, a cellular group important for the genesis of limbic seizures.Methods: We induced status epilepticus in rats, by using lithium-pilocarpine, and then 2-12 weeks later, used whole-cell voltage-clamp to examine voltage-activated sodium currents of acutely dissociated layer V neurons.Results: Transient sodium currents of entorhinal cortex layer V neurons isolated from 9-to 12-week post-status epilepticus rats were similar to currents in age-matched controls; however, low-threshold persistent sodium currents were significantly larger. This increase in persistent activity was not seen 2-3 weeks after pilocarpine treatment; thus it occurred after a delay comparable to the delay in the appearance of spontaneous seizures.Conclusions: Increased persistent currents are expected to accentuate neuronal excitability and thus may contribute to the genesis of spontaneous seizures after status epilepticus. Key Words: Pilocarpine-Voltage-gated sodium channel-Patch-clamp.Voltage-gated sodium channels provide the predominant voltage-activated excitatory current in brain neurons. Increasing evidence has linked abnormal sodium channel function to the etiology of epilepsy. For example, mutations in sodium channel genes cause inherited generalized epilepsy syndromes (1). Changes in the expression and function of wild-type sodium channels also may be involved in the epileptogenesis. Various animal models of temporal lobe epilepsy (TLE) are associated both with changes in the levels of messenger RNAs (mRNAs) for different sodium channel subtypes (2-4) and with modulation of sodium current behavior (5,6). Alterations in sodium channel mRNA also have been described in tissue samples from human TLE patients (7,8). These studies have focused on the hippocampus; however, none has specifically investigated sodium channel behavior in the entorhinal cortex (EC), which forms the principal interface between the hippocampus and neocortex and has been implicated in the genesis of ictal activity associated with TLE (9). In the present study, we demonstrate an increase in a low-threshold persistent sodium current in projection neurons from layer V of rat medial EC, after lithium-pilocarpine-induced status epilepticus (SE), a model of human TLE (10). This change in persistent current is consistent with neuronal hyperexcitability and thus may contribute to epileptogenesis in post-SE animals. MATERIALS AND METHODSMale Long-Evans rats (Charles River; P35-P47) were injected with LiCl (127 mg/kg, all injections were i.p.), and the next day injected with scopolamine methyl bromide (1 mg/kg), followed 15 min later with pilocarpine hydrochloride (30 mg/kg). Only rats showing category V ...

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Changes in the mRNAs encoding voltage-gated sodium channel types II and III in human epileptic hippocampus

Cited by 71 publications

References 54 publications

Sodium-potassium ATPase emerges as a player in hippocampal phenotypes of Angelman syndrome mice

Sodium-potassium ATPase emerges as a player in hippocampal phenotypes of Angelman syndrome mice

In Silico Docking and Electrophysiological Characterization of Lacosamide Binding Sites on Collapsin Response Mediator Protein-2 Identifies a Pocket Important in Modulating Sodium Channel Slow Inactivation

Increased Persistent Sodium Currents in Rat Entorhinal Cortex Layer V Neurons in a Post–Status Epilepticus Model of Temporal Lobe Epilepsy

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