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

Sci Rep. 2021 May 13;11(1):10256. doi: 10.1038/s41598-021-89820-1.

Abstract

N-type voltage-gated calcium channels (CaV2.2) are predominantly expressed at presynaptic terminals, and their function is regulated by auxiliary α2δ and β subunits. All four mammalian α2δ 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 α2δ-1, like α2δ-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 α2δ-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 α2δ-1 to increase CaV2.2 expression on the cell-surface of hippocampal neurites. In contrast, α2δ-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 α2δ-1, but not α2δ-3. Taken together these data suggest that α2δ subtypes participate in distinct trafficking pathways which in turn influence the localisation and function of CaV2.2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Calcium / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Channels / physiology
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Calcium Channels, N-Type / genetics
  • Calcium Channels, N-Type / metabolism
  • Cell Line
  • Cell Membrane / metabolism
  • Cyclohexanecarboxylic Acids / metabolism
  • Gabapentin / metabolism
  • Hippocampus / metabolism
  • Neurites / metabolism
  • Neurons / metabolism
  • Presynaptic Terminals / metabolism
  • Primary Cell Culture
  • Protein Transport
  • Rats
  • gamma-Aminobutyric Acid / metabolism
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Cacna2d1 protein, rat
  • Cacna2d3 protein, rat
  • Calcium Channels
  • Calcium Channels, L-Type
  • Calcium Channels, N-Type
  • Cyclohexanecarboxylic Acids
  • gamma-Aminobutyric Acid
  • Gabapentin
  • rab11 protein
  • rab GTP-Binding Proteins
  • Calcium