A bi-directional binding site linking the α2δ-1 subunit to the intrinsic speed control process in VSD I of voltage-gated calcium channels

Abstract Voltage-gated calcium channels communicate electrical signals in membranes of excitable cells into cellular responses like secretion of hormones and neurotransmitters, or the contraction of heart and skeletal muscle cells. Their activation properties are tuned to match their specific functions. Consequently, the different members of the calcium channel family activate over a wide range of voltages and with greatly differing speeds. The skeletal muscle CaV1.1 and the cardiac/neuronal CaV1.2 represent two structurally closely related channels with particularly slow and fast activation kinetics, respectively. Both channel paralogs associate with the auxiliary calcium channel subunit α2δ-1, which is a known regulator of activation properties. By expressing CaV1.1 and CaV1.2 with and without α2δ-1 in a new double-knockout muscle cell line, we demonstrate that α2δ-1 regulates activation kinetics of the two channels in opposite directions. Molecular dynamics simulation revealed a string of charged amino acids connecting α2δ-1 to the intrinsic speed-control mechanism of voltage-sensing domain I (VSD I) in CaV1.1. Charge-neutralizing mutations of any of these charged amino acids abolished the α2δ-1 modulation and accelerated current kinetics. Together, these results reveal the molecular mechanism by which the α2δ-1 subunit regulates the intrinsic speed-control mechanism in the VSD I of CaV1.1 calcium channels. Competing Interest Statement The authors have declared no competing interest.