Abstract Neuronal excitability is determined by the flux of ions through ion channels. Many types of ion channels are expressed in the central nervous system, each responsible for its own aspect of neuronal excitability, from postsynaptic depolarization to action potential generation to neurotransmitter release. These mechanisms are tightly regulated to create a balance between excitation and inhibition. Disruption of this balance is thought to be key in many neurological disorders, including epilepsy syndromes. More and more ion channel mutations are being identified through genetic studies; however, their incidence is still small, suggesting the presence of undiscovered mutations or other causative mechanisms. Understanding wild-type channel function during epileptic activity may also provide vital insights into the remaining idiopathic epilepsies and provide targets for future antiepileptic drugs. Epilepsy is one of the most common neurological disorders affecting 2% of the world&apos;s population. It varies widely in type and severity of seizures and should not be considered as a single disorder. It is currently defined as &apos;a tendency to have unprovoked recurrent seizures&apos;. Epilepsy can result from brain injury caused by head trauma, stroke or infection, but in 6 out of 10 people seizures have no known cause. Seizures are the result of excessive neuronal firing temporarily disrupting neuronal signalling. This aberrant brain activity is the result of a shift in the balance between excitation and inhibition created by ion channels. Signal transduction in neurons is controlled by electrical signals created by ion flux across the plasma membrane  Excitatory ion channels iGluRs (ionotropic glutamate receptors) would be expected to play a major role in the hyperexcitable state in epileps

S M Mizielinska

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Ion Channels 1077
Ion channels in epilepsy
S.M. Mizielinska1
Neurosciences Institute, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, U.K.
Abstract
Neuronal excitability is determined by the flux of ions through ion channels. Many types of ion channels are
expressed in the central nervous system, each responsible for its own aspect of neuronal excitability, from
postsynaptic depolarization to action potential generation to neurotransmitter release. These mechanisms
are tightly regulated to create a balance between excitation and inhibition. Disruption of this balance is
thought to be key in many neurological disorders, including epilepsy syndromes. More and more ion channel
mutations are being identified through genetic studies; however, their incidence is still small, suggesting
the presence of undiscovered mutations or other causative mechanisms. Understanding wild-type channel
function during epileptic activity may also provide vital insights into the remaining idiopathic epilepsies
and provide targets for future antiepileptic drugs.
Epilepsy is one of the most common neurological disorders
affecting 2% of the world’s population. It varies widely in
type and severity of seizures and should not be considered as
a single disorder. It is currently defined as ‘a tendency to have
unprovoked recurrent seizures’. Epilepsy can result from
brain injury caused by head trauma, stroke or infection, but in
6 out of 10 people seizures have no known cause. Seizures are
the result of excessive neuronal firing temporarily disrupting
neuronal signalling. This aberrant brain activity is the result
of a shift in the balance between excitation and inhibition
created by ion channels. Signal transduction in neurons is con-
trolled by electrical signals created by ion flux across the
plasma membrane (Figure 1). Positive ion influx upon activ-
ation of excitatory receptors (depolarization) competes with
negative ion influx through inhibitory receptors (hyperpol-
arization). Only if the depolarization is sufficient are sodium
channels at the axon hillock activated, giving rise to a transient
depolarization terminated by delayed potassium channel
activation. The depolarization activates nearby sodium
channels and is propagated along the axon to presynaptic
termini. Here, the depolarization opens calcium channels
that stimulate neurotransmitter release, which activates the
next neuron in the network, allowing information flow in
the brain. Dysfunctions of any of the ion channels involved
in this pathway are therefore prime candidates for potential
causal agents or possible targets for future antiepileptic drugs.
Excitatory ion channels
iGluRs (ionotropic glutamate receptors) would be expected
to play a major role in the hyperexcitable state in epilepsy
Key words: action potential, antiepileptic drug, epilepsy mutation, ion channel, neuronal
excitability, trafficking.
Abbreviations used: ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; AMPA, α-
amino-3-hydroxy-5-methylisoxazole-4-propionic acid; CNS, central nervous system; GABA, γ -
aminobutyric acid; GABAA, GABA type A; GABAAR, GABAA receptor; GEFS, generalized epilepsy
with febrile seizures; iGluR, ionotropic glutamate receptor; nAChR, nicotinic acetylcholine
receptor.
1email s.m.mizielinska@dundee.ac.uk
syndromes due to their excitatory actions in the CNS (central
nervous system). However, unlike other ion channels, no
mutations have yet been identified in inheritance studies.
Antagonists of iGluRs such as AMPA (α-amino-3-hydroxy-
5-methylisoxazole-4-propionic acid) receptors and NMDA
(N-methyl-D-aspartate) receptors have been shown to have
protective effects on in vitro models of epilepsy, but also
display neurological side effects in humans [1]. AMPA
receptor antagonists may have a therapeutic use in the
emergency condition status epilepticus where side effects are
less important, and also have the advantage over current drugs
that they do not impair cardiovascular function and may
protect against glutamate-induced excitotoxicity. Two new
antiepileptic drugs, topiramate and felbamate, do have effects
on glutamatergic excitatory transmission, but it is not fully
confirmed whether this is their only mechanism of action.
Inhibitory ion channels
A reduction in GABA (γ -aminobutyric acid) inhibition has
long been implicated in epilepsy, with GABAAR [GABAA
(GABA type A) receptor] antagonists promoting epileptic
seizures and agonists exhibiting anticonvulsant activity.
Enhancement of GABAA inhibitory transmission is the
primary mechanism of benzodiazepines and phenobarbital
and is a mechanistic approach to the development of novel
antiepileptic drugs. These include tiagabine, which blocks
GABA re-uptake, and vigabatrin, which blocks GABA
metabolism. A number of GABAAR mutations associated
with epilepsy have been discovered in the α1-, γ 2- and
δ-subunit genes (GABRA1, GABRG2 and GABRD). Each
mutation is reported to cause a reduction in GABAergic
inhibition and thus hyperexcitability of neurons [2]. The
R43Q mutation found in the γ 2-subunit of patients with
childhood absence epilepsy or febrile seizures causes
retention of receptors in the endoplasmic reticulum recently
found to be due to the perturbation of the β–γ interface. The
γ 2(K289M) GEFS (generalized epilepsy with febrile seizures)
C©The Authors Journal compilation C©2007 Biochemical Society
1078 Biochemical Society Transactions (2007) Volume 35, part 5
Figure 1 The role of ion channels in neuronal signalling anticonvulsant activity
mutation exhibits changes in physiology consistent with its
position in the extracellular loop implicated in channel gating.
The α1(A322D) mutation associated with juvenile myoclonic
epilepsy has been reported to be retained in the endoplasmic
reticulum where it is degraded, like the γ 2(R43Q) mutation,
decreasing the cell-surface expression and GABA potency.
Mutations in the δ-subunit are associated with GEFS
(E177A) or juvenile myoclonic epilepsy (R220C) and are
both located within the extracellular N-terminal domain,
displaying reduced current amplitudes and cell-surface
expression. In addition to the genetic predisposition in
epilepsy, a reduction in GABAAR function is also induced
by epileptic activity as a result of receptor endocytosis [3,4].
Indeed, receptors containing mutations in the γ -subunit but
not the α-subunit have been reported to exhibit impaired
trafficking or accelerated endocytosis at raised temperatures
that may be relevant to febrile seizures [5].
The gene encoding the voltage-gated chloride channel
CLC-2 (CLCN2) was first identified in a susceptibility locus
for common idiopathic epilepsies. Three mutations have now
been identified in the gene: two truncations causing loss of
function and one single-residue substitution resulting in a
change in voltage dependence [6]. Disruption of CLC-2 chan-
nel function could perturb the maintenance of the transmem-
brane chloride gradient essential for GABAAR inhibition.
Voltage-gated ion channels involved in
action potentials
Sodium channel inhibition is already the target of antiepileptic
drugs on the market, including carbamazepine, phenytoin
and lamotrigine, and may also be the mechanism for
other classic drugs. This is an obvious target for anti-
epileptic treatment as sodium channels are responsible for
the excitatory depolarization in the rising phase of an action
potential and enhanced channel activity promotes neuronal
hyperexcitability. Voltage-gated sodium channels consist of a
pore-forming α-subunit and two small accessory β-subunits
that modulate channel kinetics. The β(C121W) missense
mutation in the SCN1B gene is primarily associated with
GEFS plus, which shifts the voltage dependence and reduces
rundown during high-frequency channel activity [7,8]. Other
mutations have been found to be associated with GEFS plus
in the α-subunit genes SCN1A and SCN2A, both of which
result in an enhanced sodium current [9]. However, more
than 100 of the mutations found in the pore-forming subunit
gene SCN1A are de novo mutations (not found in either
parent) and have been reported to be associated with more
severe epileptic conditions, mutations confusingly resulting
in both increased and decreased function of the channel.
Potassium channels are essential in the repolarization and
hyperpolarizing overshoot in action potentials. Mutations in
KCNQ2 and KCNQ3, the pore-forming subunits for the M-
current known to regulate action potential initiation, are the
substrates for benign familial neonatal convulsions [10–12].
More than 50 mutations have been identified, which result
in up to a 60% reduction (or complete ablation) in current
amplitude or disrupt the residues required for calmodulin
binding and regulation [13]. The rare syndrome, episodic
ataxia type 1, has been closely associated with mutations in
the KCNA1 gene, which have been shown to result in up to a
95% reduction in current amplitudes and dominant-negative
effects on wild-type subunits [8]. The KCNQ family is
an important new target for antiepileptic drugs, such as
retigabine, identified using an in vivo screening approach
for compounds with potent activity in animal models of
epileptic seizures distinct from known anticonvulsants, and
has relatively mild side effects compared with other drugs.
Ion channels involved in neurotransmitter
release
Calcium channels are key mediators of calcium entry
into neurons in response to membrane depolarization,
mediating a number of essential functions including the
release of neurotransmitters and the regulation of neuronal
excitability. Missense mutations have been identified in genes
encoding low-voltage-activated T-type channels (Cav3.2,
C©The Authors Journal compilation C©2007 Biochemical Society
Ion Channels 1079
CACNA1H; Cav3.1, CACNA1G), high-voltage-activated
P/Q-type channels (Cav2.1, CACNA1A) and the regulatory
auxiliary β4-subunit (CACNB4). These have been mainly
associated with absence epilepsies, and the anti-absence
effect of ethosuximide is due to the inhibition of thalamic
T-type channels [14]. Some of the T- and P/Q-type channel
mutants display a hyperpolarizing shift in the voltage
dependence of activation in transient expression systems
resulting in increased channel activity, and thus increase
their subsequent activation of neurotransmitter release,
whether solely excitatory (T-type) or both excitatory and
inhibitory (P/Q-type) neurotransmission. However, most
of the mutations do not significantly affect the biophysical
characteristics of the channel; a few have been shown to affect
alternative splicing [15]. The other auxiliary subunits (α2δ2
and γ ) have also been implicated in epilepsy by mutations in
their genes (CACNA2D2 and CACNG2/4) associated with
mouse strains prone to seizures, although no mutations have
yet been identified in these genes in humans. α2δ2 ligands
such as gabapentin and pregabalin are an evolving drug class
that binds to hyperexcited calcium channels characterized
by their reduction of excessive neurotransmitter release [16].
Mutations in the nAChR (nicotinic acetylcholine receptor)
subunits are associated with the rare epilepsy syndrome AD-
NFLE (autosomal dominant nocturnal frontal lobe epilepsy),
characterized by partial seizures predominantly during sleep.
Identified missense mutations in the transmembrane regions
of α4- (CHRNA4) and β2- (CHRNB2) subunits, two of the
common nAChR subunits in the CNS, appear to reduce the
calcium potentiation of channels [17]. A mutation identified
in the neuromuscular junction nAChR α2-subunit is also
associated with ADNFLE, which increases the receptor’s
sensitivity to acetylcholine [18]. It has been proposed that
reductions in channel activity may decrease inhibitory neur-
otransmitter release or enhance excitatory neurotransmitter
release by relieving presynaptic inhibition. Although this
mechanism is still not fully understood, the involvement of
nAChRs in ADNFLE is supported by the good response of
patients to carbamazepine, an inhibitor of nAChRs.
Concluding remarks
Ion channels are prime candidates for potential causal
agents or targets for future antiepileptic drugs, due to their
individual roles in neuronal excitability. The understanding of
the structure–function relationships of ion channels and their
role in hyperexcitability has been greatly enhanced by the
analysis of mutations identified by genetic studies in familial
epilepsies. It must be noted, however, that epilepsy mutations
have only been identified in a few per cent of cases worldwide.
Moreover, the presence of an epilepsy mutation often leads
to increased susceptibility rather than an epilepsy phenotype.
Many epilepsy syndromes are also complex and polygenic,
involving environmental factors and de novo mutations.
Some of these mutations affect the trafficking of the channels
to the cell surface, but as seen with the GABAARs, wild-type
channel trafficking can also be affected. Auxiliary proteins
that regulate ion channel function and trafficking may also
contribute; mutations have recently been identified in LGI1,
associated with KCNA potassium channels, and EFHC1,
reported to increase R-type calcium currents [17]. Further
studies characterizing ion channel mutations and trafficking
during in vitro models of epilepsy, in combination with
elucidating the mechanisms of action of effective antiepileptic
drugs are needed to develop targets with specific actions and
therefore fewer neurological or peripheral side effects.
S.M.M. is supported by a BBSRC (Biotechnology and Biological
Sciences Research Council) CASE (Co-operative Awards in Science
and Engineering) studentship with Merck, Sharpe and Dohme.
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Received 24 July 2007
doi:10.1042/BST0351077
C©The Authors Journal compilation C©2007 Biochemical Society


Ion channels in epilepsy

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Ion channels in epilepsy

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