Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α(2)δ-1 but not α(2)δ-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.