Voltage-gated calcium channels (Ca_V) are large multisubunit transmembrane proteins that control calcium entry into cells in response to membrane depolarization. These channels play central roles in critical physiological processes such as generation and control of the cardiac action potential, EC coupling in heart and skeletal muscle, hormone and neurotransmitter release, and the initiation of electrical activity dependent transcriptional events. Ca_V protein complexes contain four essential subunits, Ca_Vα1, Ca_Vβ, and Ca_Vα2δ, the ubiquitous calcium sensor calmodulin (CaM). An additional subunit, Caγ, is associated with skeletal muscle channels but its general importance for Ca_V channel complexes in other tissues is unclear.

Domain structure of CaVβ. SH3 domain is shown in green, nucleotide kinase domain is shown in blue, and the AID from the alpha subunit is shown in red. Variable loops are indicated as V1, V2, and V3.

Calcium influx is a potent activator of intracellular signaling pathways but is toxic in excess. Therefore, its entry into cells is tightly regulated. Because Ca_Vs are major sources of activity dependent calcium influx, their activity is strongly controlled by both self regulatory and extrinsic mechanisms that tune their action in response to ongoing electrical activity, neurotransmitter stimulation, and hormone initiated cues. Ca_Vβs and CaM play critical roles in the intrinsic mechanisms of both calcium and voltage dependent regulation through interactions with Ca_Vα1 intracellular domains. The richness of Ca_V extrinsic regulatory mechanisms extends to modulation by G protein γ subunit, kinases and phosphatases, scaffolding molecules, and components of the synaptic vesicle release machinery. Each regulatory component interacts with one or more of the large Ca_Vα1 subunit intracellular domains the to affect the conformational changes that open or close the channel pore.

Model for how CaVβ influences channel inactivation by modulating the movement of the alpha subunit transmembrane domain IS6.

Our laboratory is pursuing high-resolution studies to uncover the basic mechanisms by which Ca_Vs function. Our determination of the structure of Ca_Vβ alone and as a complex with a portion of the I-II loop from the pore-forming subunit provided the first insight into how Ca_Vβs affect channel activity (Van Petegem et al., 2004). The lab is actively engaged in further study of this and other key channel components so that Ca_V function can be understood at the atomic level.

Structure of the Ca2+/CaM-CaV1.2 IQ domain. Ca2+/CaM N-lobe is shown in green, Ca2+/CaM C-lobe is shown in blue, and the IQ domain is shown in red. The two color shades represent two different crystallographically observed conformations.

Our laboratory is pursuing high-resolution studies to uncover the basic mechanisms by which Ca_Vs function. Our determination of the structure of Ca_Vβ alone and as a complex with a portion of the I-II loop from the pore-forming subunit provided the first insight into how Ca_Vs affect channel activity (Van Petegem et al., 2004). The lab is actively engaged in further study of this and other key channel components so that Ca_V function can be understood at the atomic level. We have recently determined the first structure of a complex of Ca²⁺/CaM together with the IQ domain from the Ca_V1.2 C-terminus (Van Petegem et al., 2005). This complex provides the first view of the machinery required for driving calcium-dependent feedback regulation of Ca_Vs and provides the necessary framework for dissection of the mechanisms of calcium dependent facilitation and calcium dependent inactivation.