Towards a Common Structure-Function Framework for Calmodulin Regulation of Calcium and Sodium Channels

Abstract

The voltage-gated calcium (CaV) and sodium (NaV) channels represent two major ion-channel superfamilies with distinct biophysical properties that support diverse biological functions. One similarity between these channels is a homologous region within their carboxy tails, the Ca2+-inactivating (CI) region. This segment, composed of two vestigial EF hands and an IQ domain, may be a conserved module enabling vital Ca2+-dependent feedback regulation through interaction with calmodulin (Cell 157:1657). A single Ca2+-free calmodulin (apocalmodulin) preassociates with the CI region, and Ca2+ binding to this calmodulin triggers regulation in both channel families. Though this general regulatory scheme appears similar between these channel families, the structural likeness of the CI region has remained unclear. Here, we correspond the first atomic structure of apocalmodulin alone bound to the NaV1.5 CI domain (Gabelli et al (2014) Nature Communications in press) with functionally relevant apocalmodulin binding residues in CaV1.3. This comparison implicates an extraordinary structural resemblance between Nav and Cav channels. But does this resemblance support like functional sequelae? Apocalmodulin binding itself enhances peak open probability of Cav channels by severalfold (Adams et al (2014) Cell in press). We now find conservation of this same effect in NaV1.4 channels. NaV1.4 channels bind apocalmodulin with high affinity and exhibit a robust open probability ∼0.4. Substituting dual alanines for the ‘IQ’ residues in the IQ element significantly weakens apocalmodulin binding, and markedly diminishes peak open probability (∼0.1). Overexpressing apocalmodulin fully rescues open probability, demonstrating that the effects on opening reflect apocalmodulin binding per se. This extensive structural and functional similarity substantiates a striking conservation of calmodulin regulation across Nav and Cav channels, joint investigation of which now presents as a genuinely synergistic endeavor.