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

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 [80]. Spikes of Cacna1aNtsr<sup>−</sup>/<sup>−</sup> mice are increased in layer VI corticothalamic neurons compared with control group, suggesting that Cav P/Q deletion generates absence epilepsy [81]. Cacna1a LOF from parvalbumin (PV)(+) 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

and excitotoxic effects in Cav2.3<sup>−</sup>/<sup>−</sup> mice compared with controls. It indicated that the Cav2.3 plays a crucial role in both hippocampal ictogenesis and seizure generalization and is of central importance in neuronal degeneration after excitotoxic events [89].
