The α2δ-1 subunit remodels CaV1.2 voltage sensors and allows Ca2+ influx at physiological membrane potentials

<div>Excitation-evoked calcium influx across cellular membranes is strictly controlled by voltage-gated calcium channels</div><div>(CaV), which possess four distinct voltage-sensing domains (VSDs) that direct the opening of a central pore.</div><div>The energetic interactions between the VSDs and the pore are critical for tuning the channel’s voltage dependence.</div><div>The accessory α2δ-1 subunit is known to facilitate CaV1.2 voltage-dependent activation, but the underlying</div><div>mechanism is unknown. In this study, using voltage clamp fluorometry, we track the activation of the four</div><div>individual VSDs in a human L-type CaV1.2 channel consisting of α1C and β3 subunits. We find that, without α2δ-1,</div><div>the channel complex displays a right-shifted voltage dependence such that currents mainly develop at nonphysiological</div><div>membrane potentials because of very weak VSD–pore interactions. The presence of α2δ-1 facilitates</div><div>channel activation by increasing the voltage sensitivity (i.e., the effective charge) of VSDs I–III. Moreover, the α2δ-1</div><div>subunit also makes VSDs I–III more efficient at opening the channel by increasing the coupling energy between</div><div>VSDs II and III and the pore, thus allowing Ca influx within the range of physiological membrane potentials.</div>