**3.1 Large conductance calciumactivated potassium channel**

Large conductance calcium-activated potassium (BK) channels, consisting of functional α subunit and the tissue-specific regulatory subunits (β1–4 and γ1–4), are widely distributed in the CNS. BK channels are usually considered as vital players in the development of epilepsy (**Figure 3**), with the evidence including the K+ derangement and regulating AP shape and duration [41, 42].

Gain-of-function mutation of BK, promoting the high-frequency neuron firing, is associated with spontaneous epileptic seizures paradoxically in both humans and rodents [43]. In fact, patients suffering from generalized epilepsy were detected a site mutation D434G at the RCK1 domain of BK α subunit. D434G increased the opening time of BK, through the enhancement of Ca2+ sensitivity [43]. In terms of functionality, the enhanced membrane excitability is associated with the increased BK activity and fAHP consequent [43, 44]. The augment seems to be induced by an increased recovery rate, underlying fast currents of VGSCs with a APs' reduced refractory period and/or through disinhibiting thalamocortical circuits by blocking brain GABAergic interneurons [43, 45, 46].

The knockout mice of BK channel β4 subunit exhibit temporal lobe epilepsy (TLE) seizure associated with a gain-of-function phenotype of BK, which not only sharpens APs but also induces a higher neuronal firing frequency in hippocampus DG granule cells [47].It is worth mentioned that epileptic seizures themselves also could induce a gain-of-function effect to BK. Picrotoxin and pentylenetetrazol (PTZ) caused generalized tonic-clonic epileptic seizures, with giving rise to a gainof-function effect on BK channels, presenting increased BK currents and neuron firing in the neocortex [48]. It is of interest that BK-specific inhibitors attenuated generalized tonic-clonic epileptic seizures in picrotoxin or PTZ-induced epilepsy models, which suppressed the increase of neuron firing [48, 49].

### **Figure 3.**

*Yin and Yang of BK channels in epilepsy. For epilepsy suppression, BK (α) channels act as negative feedback regulators on calcium rise and transmitter release in most synapses. Activation of mitoBK channel subtypes (α or α+β4) may contribute to suppressing seizure as well as conferring neuroprotection via the inhibition of ROS synthesis [54]. For epilepsy promotion, astrocyte and OPCs BK channel subtypes (α+β1 or α+β4) may induce elevate [K<sup>+</sup> ]o, causing membrane depolarization as well as neuronal hyperexcitation. Microglial BK channels (α+β3) may involve in the neuroinflammation during status epilepsy. Mutation D434G of α causes the neurohyperexcitation in hereditary epilepsy. However, ubiquitin ligase CRL4ACRBN could inhibit the overactivation of BK channels.*

**177**

*Ion Channels in Epilepsy: Blasting Fuse for Neuronal Hyperexcitability*

**3.2 Voltage-gated potassium channel subfamily KQT (KCNQ )**

of KCNQ is associated with many diseases.

rectifier K+

Kv7 is its seventh member of Kv channel family (Kv1–Kv12). The Kv7.1 mutation mediates type 1 long QT syndrome (long-QT syndrome type 1, LQT1) and is therefore named KCNQ1 (K, potassium; CN, channel; Q, LQT). KCNQ has five subtypes of KCNQ1–KCNQ5, which play crucial roles in physiological functions. Dysfunction

current and maintains the normal repolarization process of cardiomyo-

KCNQ1 is mainly distributed in the heart, which mediates cardiac delayed-

cytes [55]. KCNQ2–KCNQ5 are mainly distributed in central and peripheral neuronal tissues, of which KCNQ2 and KCNQ3 are distributed in brain regions [56]. KCNQ2 and KCNQ3 form functional heterotetramers, which are the main molecular bases for the formation of M currents that can be inhibited by acetylcholine M1 receptor activation [57]. Abundant KCNQ2 and KCNQ3 mutations could induce abnormal M currents, causing similarities in neonatal seizures and other nervous system diseases. Benign familial neonatal seizure (BFNS) is an autosomal dominant idiopathic epilepsy syndrome that occurs on the 2nd to 8th day after birth and stops spontaneously after a few weeks. Whereas 15% of patients in later life may have recurrence of epilepsy [58]. With the study of pathogenic genes in epilepsy, 60–70% of patients with BFNS were found to be associated with KCNQ2 and KCNQ3 mutations. More than 80 different mutations have been reported on KCNQ2, and multiple mutations on KCNQ3 are associated with BFNS. Soldovieri et al. [58] studied the genes of 17 BFNS clinical patients. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, 3 insertions/deletions, and 3 large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. Borgatti studied a BFNS family with four affected members: two of them exhibit BFNS only, while the other two, in addition to BFNS, present either with a severe epileptic encephalopathy or with focal seizures and mental retardation. All affected members of this family carry a novel missense mutation in the KCNQ2 gene (K526N), disrupting the tridimensional conformation of a C-terminal region of the channel subunit involved in accessory protein binding. When heterologously expressed in CHO cells, potassium channels containing mutant subunits in homomeric or heteromeric configuration with wild-type KCNQ2 and KCNQ3 subunits

Loss-of-function phenotype of BK might also contribute to the pathological process of clinical TLE. It was reported that two siblings suffered from the severe cerebellar atrophy and developmental delay, who adopted the exome analysis that identified a homozygous frameshift duplication in BK gene *KCNMA1* (c.2026dupT; p.(Tyr676 Leufs\*7)) in children from a consanguineous family with epilepsy [50]. *KCNMB3*, encoding the auxiliary BK β3, mapping the human chromosome 3 (3q26.3-q27) [51], is duplicated in the dup (3q) syndrome, which is characterized by neurological abnormalities, especially epileptic seizures [51]. Because of the dup (3q) syndrome having early onset during developmental process, the *KCNMB3* duplication implies that β3 subunits overexpression might contribute to the etiology of epilepsy. Similarly, site mutations might also contribute to both neurohyperexcitation by a single nucleotide deletion at *KCNMB3* exon 4 (delA750), which is associated with the generalized epilepsy, especially in the form of the typical absence epilepsy [52]. BK coexpressed with β3 variant of β3b-V4 (delA750) shows fast inactivation properties [53], which suggest that BK currents were reduced and the repolarization of cell membrane was attenuated during an action potential, eventually leading to neurohyperexcitation.

*DOI: http://dx.doi.org/10.5772/intechopen.83698*

### *Ion Channels in Epilepsy: Blasting Fuse for Neuronal Hyperexcitability DOI: http://dx.doi.org/10.5772/intechopen.83698*

*Epilepsy - Advances in Diagnosis and Therapy*

brain GABAergic interneurons [43, 45, 46].

**3.1 Large conductance calciumactivated potassium channel**

derangement and regulating AP shape and duration [41, 42].

models, which suppressed the increase of neuron firing [48, 49].

Large conductance calcium-activated potassium (BK) channels, consisting of functional α subunit and the tissue-specific regulatory subunits (β1–4 and γ1–4), are widely distributed in the CNS. BK channels are usually considered as vital players in the development of epilepsy (**Figure 3**), with the evidence including the K+

Gain-of-function mutation of BK, promoting the high-frequency neuron firing, is associated with spontaneous epileptic seizures paradoxically in both humans and rodents [43]. In fact, patients suffering from generalized epilepsy were detected a site mutation D434G at the RCK1 domain of BK α subunit. D434G increased the opening time of BK, through the enhancement of Ca2+ sensitivity [43]. In terms of functionality, the enhanced membrane excitability is associated with the increased BK activity and fAHP consequent [43, 44]. The augment seems to be induced by an increased recovery rate, underlying fast currents of VGSCs with a APs' reduced refractory period and/or through disinhibiting thalamocortical circuits by blocking

The knockout mice of BK channel β4 subunit exhibit temporal lobe epilepsy (TLE) seizure associated with a gain-of-function phenotype of BK, which not only sharpens APs but also induces a higher neuronal firing frequency in hippocampus DG granule cells [47].It is worth mentioned that epileptic seizures themselves also could induce a gain-of-function effect to BK. Picrotoxin and pentylenetetrazol (PTZ) caused generalized tonic-clonic epileptic seizures, with giving rise to a gainof-function effect on BK channels, presenting increased BK currents and neuron firing in the neocortex [48]. It is of interest that BK-specific inhibitors attenuated generalized tonic-clonic epileptic seizures in picrotoxin or PTZ-induced epilepsy

*Yin and Yang of BK channels in epilepsy. For epilepsy suppression, BK (α) channels act as negative feedback regulators on calcium rise and transmitter release in most synapses. Activation of mitoBK channel subtypes (α or α+β4) may contribute to suppressing seizure as well as conferring neuroprotection via the inhibition of ROS synthesis [54]. For epilepsy promotion, astrocyte and OPCs BK channel subtypes (α+β1 or α+β4) may* 

*channels (α+β3) may involve in the neuroinflammation during status epilepsy. Mutation D434G of α causes the neurohyperexcitation in hereditary epilepsy. However, ubiquitin ligase CRL4ACRBN could inhibit the* 

*]o, causing membrane depolarization as well as neuronal hyperexcitation. Microglial BK* 

**176**

**Figure 3.**

*induce elevate [K<sup>+</sup>*

*overactivation of BK channels.*

Loss-of-function phenotype of BK might also contribute to the pathological process of clinical TLE. It was reported that two siblings suffered from the severe cerebellar atrophy and developmental delay, who adopted the exome analysis that identified a homozygous frameshift duplication in BK gene *KCNMA1* (c.2026dupT; p.(Tyr676 Leufs\*7)) in children from a consanguineous family with epilepsy [50].

*KCNMB3*, encoding the auxiliary BK β3, mapping the human chromosome 3 (3q26.3-q27) [51], is duplicated in the dup (3q) syndrome, which is characterized by neurological abnormalities, especially epileptic seizures [51]. Because of the dup (3q) syndrome having early onset during developmental process, the *KCNMB3* duplication implies that β3 subunits overexpression might contribute to the etiology of epilepsy. Similarly, site mutations might also contribute to both neurohyperexcitation by a single nucleotide deletion at *KCNMB3* exon 4 (delA750), which is associated with the generalized epilepsy, especially in the form of the typical absence epilepsy [52]. BK coexpressed with β3 variant of β3b-V4 (delA750) shows fast inactivation properties [53], which suggest that BK currents were reduced and the repolarization of cell membrane was attenuated during an action potential, eventually leading to neurohyperexcitation.
