Label="BACKGROUND/AIMS" NlmCategory="OBJECTIVE">Still in 1999 the first hints were published for the pharmacoresistant Ca<sub>v</sub>2.3 calcium channel to be involved in the generation of epileptic seizures, as transcripts of alpha1E (Ca<sub>v</sub>2.3) and alpha1G (Ca<sub>v</sub>3.1) are changed in the brain of genetic absence epilepsy rats from Strasbourg (GAERS). Consecutively, the seizure susceptibility of mice lacking Ca<sub>v</sub>2.3 was analyzed in great detail by using 4-aminopyridine, pentylene-tetrazol, N-methyl-D-aspartate and kainic acid to induce experimentally convulsive seizures. Further, &#947;-hydroxybutyrolactone was used for the induction of non-convulsive absence seizures. For all substances tested, Ca<sub>v</sub>2.3-competent mice differed from their knockout counterparts in the sense that for convulsive seizures the deletion of the pharmacoresistant channel was beneficial for the outcome during experimentally induced seizures [1]. The antiepileptic drug lamotrigine reduces seizure activity in Ca<sub>v</sub>2.3-competent but increases it in Ca<sub>v</sub>2.3-deficient mice. In vivo, Ca<sub>v</sub>2.3 must be under tight control by endogenous trace metal cations (Zn<sup>2+</sup> and Cu<sup>2+</sup>). The dyshomeostasis of either of them, especially of Cu<sup>2+</sup>, may alter the regulation of Ca<sub>v</sub>2.3 severely and its activity for Ca<sup>2+</sup> conductance, and thus may change hippocampal and neocortical signaling to hypo- or hyperexcitation.