Treatment of CaV1.2 Channelopathies May Be Complicated by Altered Channel Inactivation

Abstract

Timothy Syndrome (TS) is a multisystem disorder, featuring neurological impairment, autism, and cardiac action-potential prolongation (long QT) with life-threatening arrhythmias. The underlying cause of TS was first described as a single point mutation (G406R) in CaV1.2 channels, which resulted in a disruption of both calcium- and voltage- dependent inactivation of the channel. Since this first discovery, a growing number of potentially arrhythmogenic CaV1.2 mutations have been found, increasing the need for targeted therapies. As many of these mutations have been shown to impair channel inactivation, calcium channel blockers (CCBs) such as verapamil and dihydropyridines (DHPs) represent a promising option for treatment, however, these CCBs often prove only partially effective for managing symptoms in these patients. We propose that this lack of efficacy is caused by attenuated channel inactivation in the mutant channels. In particular, verapamil and DHPs are known to preferentially block open and inactivated channels such that loss of entry into the inactivated state would decrease the efficacy of these CCBs on the mutant channels. Here, we demonstrate that mutations in CaV1.2 which diminish channel inactivation also decrease the extent of channel block by CCBs. Furthermore, we show that amount of channel block by these CCBs is strongly correlated to the fraction of inactivation in the channel, whereby efficacy of block is lowest in mutant channels with the lowest fraction of inactivation. This decreased efficacy of CCBs on mutant channels represents a major impediment to the treatment of TS and cardiac arrhythmias caused by mutations in CaV1.2. These results emphasize the need to tailor patient therapies to the specific channel deficit produced by each mutation.