**4. Calcium channels**

As an important second messenger, Ca2+ plays a vital role in normal brain function and in the pathophysiological process of different neurodegenerative diseases. Ca2+ entry via VGCCs conveys the electric signals to intracellular transduction cascades in a wide variety of cells [71]. VGCCs were first identified by Fatt and Katz [72] and shown to consist of several subunits [73, 74]. VGCCs were divided into low-voltageactivated (LVA) and high-voltage-activated (HVA), based on electrophysiological and

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

enhancing the expression of the α subunit of γ-GABAAR [79].

epilepsy [81]. Cacna1a LOF from parvalbumin (PV)(+)

pharmacological properties. HVA channels, composed of α1, β, α2δ, γ subunit, are further divided into L, N, P, and Q types, which have an activation threshold at membrane voltage positive to −20 mV [75]. LVA channels, also called T type, consist only of the α<sup>1</sup> subunit, activated at a membrane voltage positive to −70 mV. It is composed of transmembrane topology with four homologous transmembrane domains, each containing

The L-type VGCC family has four members, Cav1.1–1.4, of which α subunits present tissue-specific expression, such as the α1D subunit in the brain. The L-type VGCC family shapes neuronal firing and activates Ca2+-dependent pathways

involved in regulation of gene expression [76]. Cav1.2 channels appear to contribute critically to the generation of febrile seizures, which was proved by testing the excitability of hippocampal pyramidal cells in rat brain slices [77]. The Wistar Albino Glaxo/Rij (WAG/Rij) model experiments suggest that L-type calcium channels play a positive role in the frequency and duration of epileptic spikes [78]. Verapamil, an L-type VGCC blocker, could significantly reduce TLE seizure,

P/Q-, N-, and R-type are corresponding to Cav2.1, Cav2.2, and Cav2.3, respectively, which initiate rapid synaptic transmission, regulated primarily by direct interaction with G proteins and SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) and secondarily by protein phosphorylation. The loss function of P/Q VGCC could lead to epileptic spikes, paroxysmal dystonia and ataxia. If P/Q VGCCs were blocked, it could disrupt the triggering synaptic neurotransmitter release

compared with control group, suggesting that Cav P/Q deletion generates absence

and somatostatin (SST)(+) interneurons results in severe generalized epilepsy. It might be the mechanism for severe generalized epilepsy that the loss of Cav2.1 channel function from cortical PV(+) interneurons inhibits GABA release from these cells, which impairs their ability to constrain cortical pyramidal cell excitability [82]. When knocking out the cerebellar Cav2.1 channel in mice, cortical function is changeable, which caused movement disorders and epilepsy [83]. In two families with idiopathic epilepsy, the loss of function mutation in γ4 subunits, auxiliary subunit of Cav2.1 channels, could also cause seizures, and maybe aggravate seizures [84]. Downregulation of α2δ2 subunits in rats will generate 5–7 Hz epileptic wave accompanied by ataxia [85]. N-type calcium channels are mainly distributed in the nucleus of different neurons and glial cells. In the pilocarpine model, Cav2.2 expression decreased in the granule layer of the dentate gyrus and the pyramidal cells of the CA3 region during the acute phase of seizure. However, the expression of N-type calcium channels increased in the subsequent chronic phase, which demonstrated that the increase of N-type calcium channels might be associated with recurrent status epilepticus [86]. R-type calcium channel, Cav2.3, is mainly distributed in the presynaptic membrane, such as hippocampal mossy fibers, globus pallidus, and neuromuscular junctions. Knocking out R-type calcium channels could increase the susceptibility of seizures, with altering the seizure form [87]. The lack of Cav2.3 resulted in a marked decrease in the sensitivity of the animal to γ-butyrolactone-induced absence epilepsy and change thalamocortical network oscillations [88]. Administration of kainic acid revealed alteration in behavioral seizure architecture, dramatic resistance to limbic seizures

mice are increased in layer VI corticothalamic neurons

six transmembrane segments and a pore region between segments S5 and S6.

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

**4.1 L-type Cav**

**4.2 P/Q-, N-, and R-type Cav**

[80]. Spikes of Cacna1aNtsr<sup>−</sup>/<sup>−</sup>

pharmacological properties. HVA channels, composed of α1, β, α2δ, γ subunit, are further divided into L, N, P, and Q types, which have an activation threshold at membrane voltage positive to −20 mV [75]. LVA channels, also called T type, consist only of the α<sup>1</sup> subunit, activated at a membrane voltage positive to −70 mV. It is composed of transmembrane topology with four homologous transmembrane domains, each containing six transmembrane segments and a pore region between segments S5 and S6.
