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All auxiliary alpha2delta subunits of voltage-gated Ca2+ (Ca(V)) channels contain an extracellular Von Willebrand factor-A (VWA) domain that, in alpha2delta-1 and -2, has a perfect metal-ion-dependent adhesion site (MIDAS). Modeling of the alpha2delta-2 VWA domain shows it to be highly likely to bind a divalent cation. Mutating the three key MIDAS residues responsible for divalent cation binding resulted in a MIDAS mutant alpha2delta-2 subunit that was still processed and trafficked normally when it was expressed alone. However, unlike WT alpha2delta-2, the MIDAS mutant alpha2delta-2 subunit did not enhance and, in some cases, further diminished Ca(V)1.2, -2.1, and -2.2 currents coexpressed with beta1b by using either Ba2+ or Na+ as a permeant ion. Furthermore, expression of the MIDAS mutant alpha2delta-2 reduced surface expression and strongly increased the perinuclear retention of Ca(V)alpha1 subunits at the earliest time at which expression was observed in both Cos-7 and NG108-15 cells. Despite the presence of endogenous alpha2delta subunits, heterologous expression of alpha2delta-2 in differentiated NG108-15 cells further enhanced the endogenous high-threshold Ca2+ currents, whereas this enhancement was prevented by the MIDAS mutations. Our results indicate that alpha2delta subunits normally interact with the Ca(V)alpha1 subunit early in their maturation, before the appearance of functional plasma membrane channels, and an intact MIDAS motif in the alpha2delta subunit is required to promote trafficking of the alpha1 subunit to the plasma membrane by an integrin-like switch. This finding provides evidence for a primary role of a VWA domain in intracellular trafficking of a multimeric complex, in contrast to the more usual roles in binding extracellular ligands in other exofacial VWA domains.

proceedings of the national academy of sciences of the united states of america

The metal-ion-dependent adhesion site in the Von Willebrand factor-A domain of α <sub>2</sub> δ subunits is key to trafficking voltage-gated Ca <sup>2</sup> + channels

The metal-ion-dependent adhesion site in the Von Willebrand factor-A domain of α 2 δ subunits is key to trafficking voltage-gated Ca 2 + channels

The metal-ion-dependent adhesion site in the Von Willebrand factor-A domain of α ₂ δ subunits is key to trafficking voltage-gated Ca ² + channels