Calcium entry through voltage-gated calcium channels (VGCCs) plays a pivotal role in diverse cellular processes including muscle contraction, neuronal excitability and gene expression. Multiple VGCC subtypes exist, that differ in their biophysical properties and distributions within and between tissues, thereby, allowing cells to tailor calcium influx to discrete functional demands. However, the mechanisms underlying this process are not yet understood. VGCCs are multi-subunit complexes that comprise a pore-forming alpha1 and two regulatory subunits: alpha2-delta and beta. Of these, the alpha2-delta subunit is an attractive candidate to drive targeting and distribution of VGCCs. Alpha2-delta subunits enhance surface expression and modify the biophysical properties of VGCCs (Bernstein and Jones, 2007). Moreover, structurally, they are similar to integrin receptors that mediate bidirectional signalling between intra- and extracellular compartments. ECM-integrin interactions are known to control growth factor-dependent signalling in sensory neurones using the major VGCC regulatory ERK1/2 pathway (Fitzgerald, 2000; Woodall et al., 2005). Thus, we hypothesize that a key role of alpha2-delta subunits may be to direct VGCCs to specific ECM-associated signalling complexes. Using a library of functional VGCC subunits each separately tagged with red, green or blue protein fluorophores, we have tested interactions between the ECM and discrete VGCC complexes. High resolution fluorescence imaging of COS-7 and HEK-293 cells transiently transfected with select VGCC complexes has confirmed the requirement for the presence of a beta subunit (beta 3) in directing exit from the endoplasmic reticulum and subsequent surface expression, of the pore-forming alpha1 subunit (Cav2.2, N-type). Alpha2-delta-1 appears to show a distinct pattern of labelling, indicative of its high cell surface expression and regionalized distribution. Polystyrene beads coated with ECM proteins (laminin-1 and fibronectin) cause a marked redistribution of VGCC complexes containing alpha2-delta-1 subunits. Ongoing experiments are defining the basis for these effects in terms of the precise subunits and regions driving these interactions and their functional consequences.