TY - JOUR T1 - Functional selectivity and partial efficacy at the monoamine transporters: a unified model of allosteric modulation and amphetamine-induced substrate release JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.118.114793 SP - mol.118.114793 AU - Peter S Hasenhuetl AU - Shreyas Bhat AU - Michael Freissmuth AU - Walter Sandtner Y1 - 2018/01/01 UR - http://molpharm.aspetjournals.org/content/early/2018/12/19/mol.118.114793.abstract N2 - All clinically approved drugs targeting the plasmalemmal transporters for dopamine, norepinephrine and serotonin act either as competitive uptake inhibitors or as amphetamine-like releasers. Recently, monoamine transporter (MAT) ligands were discovered that allosterically affect MAT-mediated substrate uptake, release, or both. Their modes of action have not been explained in a unified framework. Here, we go beyond competitive inhibitors and classical amphetamines and introduce concepts for partial efficacy at and allosteric modulation of MATs. After elaborating a kinetic account for amphetamine action, we provide an explanation for partial release, i.e. the observation that some amphetamines are less efficacious than others in inducing monoamine efflux. We then elucidate mechanisms of allosteric inhibition and stimulation of MATs, which can be functionally selective for either substrate uptake or amphetamine-induced release. These concepts are integrated into a parsimonious kinetic framework, which relies exclusively on physiological transport modes (without any deviation from an alternating access mechanism). The model posits cooperative substrate- and Na+-binding and functional selectivity by conformational selection, i.e. preference of the allosteric modulators for the substrate-loaded or substrate-free states of the transporter. Thus, the current knowledge about the kinetics of monoamine transport is sufficiently detailed to provide a quantitative description of the releasing action of amphetamines, of substrate uptake, and of selective modulation thereof by allosteric modulators. ER -