Mechanisms by which calcium regulates the human cardiac voltage-gated sodium channel hH1

Abstract

The function of the human cardiac voltage-gated sodium channel hH1 is regulated in part by an EF-hand in its C-terminal cytoplasmic domain. The binding of calcium to the EF-hand results in calmodulin-independent, calcium-dependent changes in channel behavior. The channel is also regulated via an extrinsic calcium sensing pathway mediated by calmodulin (CaM), which binds to an IQ motif immediately adjacent to the EF-hand domain. Our results demonstrate the presence of these sensors and suggest that they are coupled through the IQ motif, which serves in this case as a molecular switch. Initially the IQ motif recruits CaM with strong affinity. When calcium levels are elevated, CaM binds calcium and undergoes a conformational change that reduces its affinity for the IQ motif. Release of the IQ motif would promote its interaction with the intrinsic calcium sensor, which raises the calcium affinity of the intrinsic sensor 1000-fold. Preliminary results suggest that Ca2+-loaded CaM binds to a remote site on hH1, supporting this hypothesized sequence of events. A comprehensive molecular mechanism for the Ca2+-dependent regulation of hH1 is proposed.