Assessing the Impact of Calmodulinopathic Mutations on Neuronal Ion Channel Regulation

Abstract

activation resembles that of relaxed VSD-II. In addition, VSD-IV voltagedependent activation was not modified by nifedipine (control: V half = À39.7mV, z= 0.72e 0 , nifedipine: V half = À40.17mV, z= 0.62e 0 ). VSD-I is currently under investigation. Overall, we found that at least two VSDs are modified by nifedipine, suggesting that the binding of the drug to the pore region of the channel allosterically modifies these VSDs activation. Indeed, a recent CaV1.1 Cryo EM structure (Zhao et al., Cell 2019) shows that VSD-II and VSD-III are the voltage sensors in closer proximity to the pore region involved in dihydropyridine binding. Alternatively, nifedipine may also directly bind to the VSDs and remodel their operation.