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 alpha (2)delta and beta subunits. All four mammalian alpha (2)delta 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 alpha (2)delta -1, like alpha (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 alpha (2)delta -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 alpha (2)delta -1 to increase Ca(V)2.2 expression on the cell-surface of hippocampal neurites. In contrast, alpha (2)delta -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 alpha (2)delta -1, but not alpha (2)delta -3. Taken together these data suggest that alpha (2)delta subtypes participate in distinct trafficking pathways which in turn influence the localisation and function of Ca(V)2.2.

Automated summary

This study reveals that different subtypes of α(2)δ participate in distinct trafficking pathways, which in turn influence the localization and function of Ca(V)2.2.