Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3

N-type voltage-gated calcium channels (Ca V 2.2) are predominantly expressed at presynaptic terminals, and their function is regulated by auxiliary α 2 δ and β subunits. All four mammalian α 2 δ subunits enhance calcium currents through Ca V 1 and Ca V 2 channels, and this increase is attributed, in part, to increased Ca V expression at the plasma membrane. In the present study we provide evidence that α 2 δ-1, like α 2 δ-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 α 2 δ-1 increases plasma membrane Ca V 2.2 expression by increasing the rate and extent of net forward Ca V 2.2 trafficking in a Rab11a-dependent manner. Dominant-negative Rab11a also reduces the ability of α 2 δ-1 to increase Ca V 2.2 expression on the cell-surface of hippocampal neurites. In contrast, α 2 δ-3 does not enhance rapid forward Ca V 2.2 trafficking, regardless of whether Rab11a(S25N) is present. In addition, whole-cell Ca V 2.2 currents are reduced by co-expression of Rab11a(S25N) in the presence of α 2 δ-1, but not α 2 δ-3. Taken together these data suggest that α 2 δ subtypes participate in distinct trafficking pathways which in turn influence the localisation and function of Ca V 2.2.