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

Abstract

N-type voltage-gated calcium channels (CaV2.2) are predominantly expressed at presynaptic terminals, and their function is regulated by auxiliary 2{delta} and {beta} subunits. All four mammalian 2{delta} subunits enhance calcium currents through CaV1 and CaV2 channels, and this increase is attributed, in part, to increased CaV expression at the plasma membrane. In the present study we provide evidence that 2{delta}-1, like 2{delta}-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 2{delta}-1 increases plasma membrane CaV2.2 expression by increasing the rate and extent of net forward CaV2.2 trafficking in a Rab11a-dependent manner. Dominant-negative Rab11a also reduces the ability of 2{delta}-1 to increase CaV2.2 expression on the cell-surface of hippocampal neurites. In contrast, 2{delta}-3 does not enhance rapid forward CaV2.2 trafficking, regardless of whether Rab11a(S25N) is present. In addition, whole-cell CaV2.2 currents are reduced by co-expression of Rab11a(S25N) in the presence of 2{delta}-1, but not 2{delta}-3. Taken together these data suggest that 2{delta} subtypes participate in distinct trafficking pathways which in turn influence the localisation and function of CaV2.2. Summary statementThe calcium channel auxiliary subunit 2{delta}-1 but not 2{delta}-3 participates in Rab11a-dependent recycling, which in turn influences the localisation and function of CaV2.2.