The structural biology of voltage-gated calcium channel function and regulation

Voltage-gated calcium channels (Ca_Vs) are large (∼0.5 MDa), multisubunit, macromolecular machines that control calcium entry into cells in response to membrane potential changes. These molecular switches play pivotal roles in cardiac action potentials, neurotransmitter release, muscle contraction, calcium-dependent gene transcription and synaptic transmission. Ca_Vs possess self-regulatory mechanisms that permit them to change their behaviour in response to activity, including voltage-dependent inactivation, calcium-dependent inactivation and calcium-dependent facilitation. These processes arise from the concerted action of different channel domains with Ca_V β-subunits and the soluble calcium sensor calmodulin. Until recently, nothing was known about the Ca_V structure at high resolution. Recent crystallographic work has revealed the first glimpses at the Ca_V molecular framework and set a new direction towards a detailed mechanistic understanding of Ca_V function.