Functional and pathological consequences of being fast on the uptake: Protein kinase G and p38α MAPK regulation of serotonin transporters

Serotonin (5-hydroxytryptamine, 5-HT) signaling plays an important role in dynamic control of peripheral and central nervous system physiology, with altered 5-HT homeostasis implicated in a significant number of disorders, ranging from pulmonary, bowel, and metabolic disease to depression, obsessive-compulsive disorder, and autism spectrum disorder (ASD). The presynaptic, 5-HT transporter (SERT) has a well-established role in regulating 5-HT signaling and is a target of widely prescribed psychotherapeutics, the 5-HT selective reuptake inhibitors (SSRIs). Although SSRI therapy provides symptom relief for many suffering from mood and anxiety disorders, response to these medications is slow (weeks), and too many receive modest or no benefit. At present, all prescribed SSRIs act as competitive SERT antagonists. Although non-serotonergic therapeutics for mood disorders deserve aggressive investigation, the development of agents that target SERT regulatory pathways have yet to be considered for their possible utility and may possibly offer improved efficacy and more rapid onset. Here, we focus attention on a significant body of evidence that SERT transport activity can be rapidly elevated by protein kinase G (PKG) and p38α mitogen activated protein kinase (MAPK) linked pathways, mechanisms that are impacted by disease-associated genetic variation. Here, we provide a brief overview of kinase-linked, posttranslational regulation of SERT, with a particular focus on evidence from pharmacological and genetic studies that the transporter's regulation by PKG/p38α MAPK associated pathways offers an opportunity to more subtly adjust, rather than eliminate, SERT function as a therapeutic strategy.