Most psychostimulant drugs interfere with the transport proteins that mediate reuptake of the monoamines dopamine, norepinephrine and serotonin into the presynaptic specialization. The majority of these drugs, like cocaine, inhibit monoamine uptake by blocking substrate binding to the cognate transport protein. On the other hand, amphetamines do not simply block reuptake; they directly reverse the transport process and induce non-vesicular monoamine release. Although this has been recognized for several decades, a quantitatively plausible mechanistic explanation has been missing. A central question has been whether the transport reactions met under physiological conditions suffice to account for amphetamine action, or whether additional – amphetamine-specific – transport modes need to be invoked.

Here, recent efforts to solve this problem in the human serotonin transporter will be summarized. The catalytic cycle of the serotonin transport process has been resolved in kinetic detail, which culminated in the formulation of a parsimonious alternating access model of serotonin transport. This model – which obeys a cooperative binding order – is sufficient to account qualitatively and quantitatively for the monoamine-releasing action of amphetamines. Hence, amphetamine-induced monoamine release can be explained without assuming any additional amphetamine-specific transport modes. Moreover, a mechanistic explanation for ‘partial release’ (i.e. that some amphetamine congeners are less efficacious releasers than others) is a direct consequence of the model. It is hoped that the framework presented here will guide further experiments to delineate the full reaction cycle of amphetamine action.

The presented work can be found in the following articles:
1.) Hasenhuetl PS*, Bhat S*, Mayer FP, Sitte HH, Freissmuth M, Sandtner W (2018) A Kinetic Account for Amphetamine-Induced Monoamine Release. Journal of General Physiology
[* shared first author; published online 09. February 2018]
2.) Bhat S, Hasenhuetl PS, Kasture A, El-Kasaby A, Baumann MH, Blough BE, Sucic S, Sandtner W, Freissmuth M (2017) Conformational State Interactions Provide Clues to the Pharmacochaperone Potential of Serotonin Transporter Partial Substrates. Journal of Biological Chemistry 292:16773-16786.
3.) Hasenhuetl PS, Freissmuth M, Sandtner W (2016) Electrogenic Binding of Intracellular Cations Defines a Kinetic Decision-Point in the Transport Cycle of the Human Serotonin Transporter. Journal of Biological Chemistry 291:25864-25876.