Disparate effects of CaM N- and C-lobe CPVT-linked mutations on SK channel-CaM assembly

Small conductance Ca2+-activated K+ (SK) channels are voltage independent and their gating is governed by Ca2+ via calmodulin (CaM) constitutively bound to the C-terminal CaM-binding domain (CaMBD). Recently, several CaM mutations have been linked to a hereditary arrhythmia syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia. Although in vitro studies demonstrated that mutations in both terminuses of CaM cause loss of SK-channel complex function, the exact mechanisms remain elusive. We hypothesize that N-terminus and C-terminus CaM mutations affect SKs differently given that CaM associates with SK via its C-terminus lobe, while CaM’s N-terminus lobe serves as a Ca2+ sensor for the complex.