Amphetamine activates calcium channels through dopamine transporter-mediated depolarization

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Amphetamine (AMPH) and S(+)AMPH are psychostimulants used for ADHD, possessing abuse potential.
• AMPH acts as a dopamine transporter (DAT) substrate, affecting dopamine uptake and release.
• AMPH-induced DAT currents can modulate cell excitability via voltage-gated channels.

Purpose of the Study:

• To investigate the electrical coupling between human DAT (hDAT) and different voltage-gated calcium channels (CaV).
• To compare the effects of S(+)AMPH and dopamine (DA) on hDAT-CaV interactions.
• To determine the influence of CaV properties and substrate affinity on this coupling.

Main Methods:

• Co-expression of hDAT with CaV1.3, CaV1.2, or CaV2.2 channels in cells.
• Measurement of inward currents and calcium (Ca2+) signals.
• Analysis of substrate potency and coupling strength.

Main Results:

• S(+)AMPH and DA activate L-type CaV1.3 and CaV1.2 channels, but not CaV2.2, at saturating concentrations.
• Substrate affinity for hDAT primarily determines coupling potency.
• Maximal coupling strength is influenced by CaV voltage sensitivity, favoring CaV1.3.
• S(+)AMPH shows greater coupling strength than DA at lower concentrations.

Conclusions:

• S(+)AMPH is a more potent inducer of hDAT-mediated L-type CaV currents than DA.
• S(+)AMPH acts as a more effective depolarizing agent, leading to tighter electrical coupling between hDAT and CaV activation.