A bi-directional binding site linking the α ₂ δ-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 _V 1.1 and the cardiac/neuronal Ca _V 1.2 represent two structurally closely related channels with particularly slow and fast activation kinetics, respectively. Both channel paralogs associate with the auxiliary calcium channel subunit α ₂ δ-1, which is a known regulator of activation properties. By expressing Ca _V 1.1 and Ca _V 1.2 with and without α ₂ δ-1 in a new double-knockout muscle cell line, we demonstrate that α ₂ δ-1 regulates activation kinetics of the two channels in opposite directions. Molecular dynamics simulation revealed a string of charged amino acids connecting α ₂ δ-1 to the intrinsic speed-control mechanism of voltage-sensing domain I (VSD I) in Ca _V 1.1. Charge-neutralizing mutations of any of these charged amino acids abolished the α ₂ δ-1 modulation and accelerated current kinetics. Together, these results reveal the molecular mechanism by which the α ₂ δ-1 subunit regulates the intrinsic speed-control mechanism in the VSD I of Ca _V 1.1 calcium channels.