**4.1 L-type Cav**

*Epilepsy - Advances in Diagnosis and Therapy*

**3.3 G protein-coupled Kir channel**

exhibit an altered voltage-dependence of activation, without changes in intracellular trafficking and plasma membrane expression. The KCNQ2 K526N mutation might affect M-channel function by disrupting the complex biochemical signaling involving KCNQ2 C-terminus [59, 60]. KCNQ2 or KCNQ3 mutations cause M current to be downregulated, and the frequency of neuronal firing increases, leading to epilepsy.

Inward-rectifier potassium channels (Kir, IRK) are a specific subset of potassium channels. To date, seven subfamilies have been identified, which are associated with a variety of diseases [61]. The G-protein-coupled Kir (GIRK) channels belong to the subfamily of Kir3 (GIRKs) which are activated by ligand-stimulated G protein-coupled receptors (GPCRs). GPCRs, interacting with GIRK channels, facilitate their activation, resulting in hyperpolarization of the cell membrane [61]. GIRK channels have four identified subunits (GIRK1–4, encoded by KCNJ3, KCNJ6, KCNJ9, and KCNJ5, respectively) in mammals, existing in vivo both as homotetramers and heterotetramers with unique biophysical properties, regulation, and distribution [61, 62]. GIRK 1, 2, 3, and 4 subunits are expressed in the brain, localized in certain axons, postsynaptic, and presynaptic regions [63]. GIRK channels may be involved not only in slow inhibitory postsynaptic potentials but

GIRK in the CNS is a heterotetramer composed of GIRK1 and GIRK2 subunits [63], which is responsible for maintaining the resting membrane potential and excitability of the neuron [64]. GIRK1 and GIRK2 subunits are found in the dendritic areas of neurons highly [63] correlate with the large concentration of GABAB receptors. Once the GABAB receptors are activated by their ligands, they can in turn activate IRK, mediating a significant part of the GABA postsynaptic inhibition [63]. Alterations in GIRK function have been associated with pathophysiology of severe brain disorders, including epilepsy. In this regard, a GIRK2 knockout mouse model resulted to be more susceptible to develop both spontaneous and induced seizures in respect to wild-type mice [65]. In particular, mice carrying a p Gly156Ser mutation displayed an epileptic phenotype [66]. Indeed, this mutation has been found to alter the putative ion-permeable, pore-forming domain of the channel, inducing Ca2+ overload in cells and reducing channel availability, leading thus to

An increased expression of GIRK was observed in rat brain after an electroconvulsive shock, probably altering the excitability of granule cells and the functions of neurotransmitter receptors which are coupled to these channels [68]. Another evidence in support of a role of GIRK in epilepsy was provided by the demonstration that ML297, a potent and selective activator of GIRK, showed epileptogenic properties in mice [69]. On the other hand, the inhibition of GIRK activity by drugs causes seizures [70]. All these considerations imply that changes in Kir3 channel

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

also in the presynaptic modulation of neuronal activity [61].

neurodegeneration and seizure susceptibility [67].

activity may alter the susceptibility to seizures.

**4. Calcium channels**

**178**

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