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

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 Ca_V1.1 and the cardiac/neuronal Ca_V1.2 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 Ca_V1.1 and Ca_V1.2 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 Ca_V1.1. 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 Ca_V1.1 calcium channels.