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

Voltage-gated calcium channels (Ca(v)s) are large (similar to 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. I 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 beta-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.