The Morbidity Of Epilepsy And Cardiac Arrhythmia Is Attributed To Common Channelopathy Of Genetic Mutants Of Slack Channels

In recent years, more and more genetic mutants of Slack channels that are associated with epilepsy, Brugada syndrome and cardiac arrhythmia have been identified from patients with epilepsy. However, whether the mutants related to cardiac arrhythmia share similar biophysical properties with mutants associated with epilepsy remains elusive. In this abstract, we characterized the biophysical properties of 13 epilepsy associated genetic mutants of Slack channels, including two mutants associated with cardiac arrhythmia. We found that 12 of total 13 mutants possess enhanced maximum Po while some of them also have enhanced sodium sensitivity. Furthermore, the patient who carried the only one mutant that has decreased Po and lower maximum Po actually has other factor that may induce epilepsy. Thus, the enhanced maximum Po and increased sodium sensitivity could be a standard to judge if a Slack channel mutant is really associated with epilepsy. In addition, two functional alternated splicing isoforms of human Slack channels have been cloned and characterized, which we name hSlackB1 and hSlackB2. When expressed in Xenopus ooctyes, robust sodium dependent potassium current were recorded from hSlackB1 and hSlackB2 constructs while no potassium current could be recorded from hSlackA construct. In the meantime, rundown of hSlackB1 activity can be observed but no rundown of hSlackB2 activity can be observed. Taken together, we concluded that Brugada syndrome, cardiac arrhythmia and epilepsy led by Slack channel mutants is common channelopathy caused by enhanced maximum Po, increased sodium sensitivity and suitable splicing.