Going with the Flow: Trafficking‐Dependent and ‐Independent Regulation of Serotonin Transport

Abstract

Antidepressant‐, cocaine‐ and 3,4‐methylenedioxymethamphetamine‐sensitive serotonin (5‐hydroxytryptamine, 5‐HT) transporters (SERTs) are expressed on presynaptic membranes of 5‐HT‐secreting neurons to provide efficient uptake of the biogenic amine after release. SERTs also support 5‐HT transport across platelet, placental, gastrointestinal and pulmonary membranes and thus play a critical role in central nervous system and peripheral nervous system 5‐HT signaling. SERTs are subject to multiple levels of posttranslational regulation that can rapidly alter 5‐HT uptake and clearance rates. Specific cell surface receptors are now known to regulate SERT trafficking and/or catalytic function, with pathways activating protein kinase C, protein kinase G and p38 mitogen‐activated protein kinase receiving the greatest attention. Remarkably, disease‐associated mutations in SERT not only impact basal SERT activity but also selectively impact one or more SERT regulatory pathway(s). In this review, we describe both trafficking‐dependent and trafficking‐independent modes of SERT regulation and also the suspected roles played in regulation by SERT‐associated proteins. Elucidation of the SERT ‘regulome’ provides important depth to our understanding of the likely origins of 5‐HT‐associated disorders and may help orient research to develop novel therapeutics.