Altered ion permeability would clearly affect intercellular signaling and may precipitate the paroxysmal episodes. But how can a channelopathy generate a prolonged paroxysmal event? The episodic events observed in FHM/EA-2 and tottering/leaner generally last for tens of minutes to tens of hours; the shortest events, the spike and wave discharges observed in tottering and leaner mice, last for several seconds. By contrast, calcium channel activation and inactivation occur on the order of milliseconds to at most seconds in vivo. It is difficult to directly reconcile the prolonged phenotypic events with the molecular events as even mutant channels are unlikely to sustain abnormal activity for such extended periods. Both exocytotic release and neuronal electrical properties are regulated by calcium channels. Therefore, given the extended expression of the episodic phenotypes, these prolonged neurologic events are likely to involve abnormal polysynaptic signaling generated or sustained by the disrupted neurotransmission.These mouse mutants may serve as direct animal models of FHM and/or EA-2. The close proximity of the tottering mutation to one of the FHM mutations suggests the functional calcium channel defect may correspond in both human and mouse. Furthermore, while the phenotypes expressed in man and mice are not identical, they are very similar, mimicking both the paroxysmal nature of the disorder and the cerebellar atrophy. Of course, it is not reasonable to expect direct phenotypic correspondence between mouse and human even where the genetic defects are identical; this is especially true for FHM since it is not clear that mice (tottering or otherwise) experience migraine headaches. Nonetheless, these mice may provide a model for understanding the relationship between migraine headaches and ion channel misregulation. The genotypic and phenotypic similarities between the channelopathies in humans and the tottering mouse mutants suggest that tottering mice will be extremely useful for determining how a channelopathy can generate prolonged paroxysmal neurologic dysfunction in humans.