Functional Selectivity and Partial Efficacy at the Monoamine Transporters: A Unified Model of Allosteric Modulation and Amphetamine-Induced Substrate Release.

All clinically approved drugs targeting the plasmalemmal transporters for dopamine, norepinephrine, and serotonin act either as competitive uptake inhibitors or as amphetamine-like releasers. Monoamine transporter (MAT) ligands that allosterically affect MAT-mediated substrate uptake, release, or both were recently discovered. Their modes of action have not yet been explained in a unified framework. Here, we go beyond competitive inhibitors and classic amphetamines and introduce concepts for partial efficacy at and allosteric modulation of MATs. After we elaborate on 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 physiologic 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, 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.