Amphetamine activates calcium channels through dopamine transporter-mediated depolarization

Cell Calcium. 2015 Nov;58(5):457-66. doi: 10.1016/j.ceca.2015.06.013. Epub 2015 Jul 2.


Amphetamine (AMPH) and its more potent enantiomer S(+)AMPH are psychostimulants used therapeutically to treat attention deficit hyperactivity disorder and have significant abuse liability. AMPH is a dopamine transporter (DAT) substrate that inhibits dopamine (DA) uptake and is implicated in DA release. Furthermore, AMPH activates ionic currents through DAT that modify cell excitability presumably by modulating voltage-gated channel activity. Indeed, several studies suggest that monoamine transporter-induced depolarization opens voltage-gated Ca(2+) channels (CaV), which would constitute an additional AMPH mechanism of action. In this study we co-express human DAT (hDAT) with Ca(2+) channels that have decreasing sensitivity to membrane depolarization (CaV1.3, CaV1.2 or CaV2.2). Although S(+)AMPH is more potent than DA in transport-competition assays and inward-current generation, at saturating concentrations both substrates indirectly activate voltage-gated L-type Ca(2+) channels (CaV1.3 and CaV1.2) but not the N-type Ca(2+) channel (CaV2.2). Furthermore, the potency to achieve hDAT-CaV electrical coupling is dominated by the substrate affinity on hDAT, with negligible influence of L-type channel voltage sensitivity. In contrast, the maximal coupling-strength (defined as Ca(2+) signal change per unit hDAT current) is influenced by CaV voltage sensitivity, which is greater in CaV1.3- than in CaV1.2-expressing cells. Moreover, relative to DA, S(+)AMPH showed greater coupling-strength at concentrations that induced relatively small hDAT-mediated currents. Therefore S(+)AMPH is not only more potent than DA at inducing hDAT-mediated L-type Ca(2+) channel currents but is a better depolarizing agent since it produces tighter electrical coupling between hDAT-mediated depolarization and L-type Ca(2+) channel activation.

Keywords: Excitability; L-type Ca(2+) channels; MDMA; Monoamine transporters; Neurotransmitter transport; Serotonin; Stimulants.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amphetamine / pharmacology*
  • Calcium / metabolism
  • Calcium Channel Agonists / pharmacology*
  • Calcium Channels / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Membrane Potentials


  • Calcium Channel Agonists
  • Calcium Channels
  • Dopamine Plasma Membrane Transport Proteins
  • Amphetamine
  • Calcium