The reverse operation of Na+/Cl−‐coupled neurotransmitter transporters – why amphetamines take two to tango

Sodium‐chloride coupled neurotransmitter transporters achieve reuptake of their physiological substrate by exploiting the pre‐existing sodium‐gradient across the cellular membrane. This terminates the action of previously released substrate in the synaptic cleft. However, a change of the transmembrane ionic gradients or specific binding of some psychostimulant drugs to these proteins, like amphetamine and its derivatives, induce reverse operation of neurotransmitter:sodium symporters. This effect eventually leads to an increase in the synaptic concentration of non‐exocytotically released neurotransmitters and – in the case of the norepinephrine transporters, underlies the well‐known indirect sympathomimetic activity]. While this action has long been appreciated, the underlying mechanistic details have been surprisingly difficult to understand. Some aspects can be resolved by incorporating insights into the oligomeric nature of transporters, into the nature of the accompanying ion fluxes, and changes in protein kinase activities.