Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit αδ-1 but not αδ-3.

N-type voltage-gated calcium channels (Ca2.2) are predominantly expressed at presynaptic terminals, and their function is regulated by auxiliary αδ and β subunits. All four mammalian αδ subunits enhance calcium currents through Ca1 and Ca2 channels, and this increase is attributed, in part, to increased Ca expression at the plasma membrane. In the present study we provide evidence that αδ-1, like αδ-2, is recycled to the plasma membrane through a Rab11a-dependent endosomal recycling pathway. Using a dominant-negative Rab11a mutant, Rab11a(S25N), we show that αδ-1 increases plasma membrane Ca2.2 expression by increasing the rate and extent of net forward Ca2.2 trafficking in a Rab11a-dependent manner. Dominant-negative Rab11a also reduces the ability of αδ-1 to increase Ca2.2 expression on the cell-surface of hippocampal neurites. In contrast, αδ-3 does not enhance rapid forward Ca2.2 trafficking, regardless of whether Rab11a(S25N) is present. In addition, whole-cell Ca2.2 currents are reduced by co-expression of Rab11a(S25N) in the presence of αδ-1, but not αδ-3. Taken together these data suggest that αδ subtypes participate in distinct trafficking pathways which in turn influence the localisation and function of Ca2.2.