Natural and engineered coding variation in antidepressant-sensitive serotonin transporters

Abstract

The presynaptic serotonin (5-HT) transporter (SERT) is a key regulator of 5-HT signaling and is a major target for antidepressant medications and psychostimulants. In recent years, studies of natural and engineered genetic variation in SERT have provided new opportunities to understand structural dimensions of drug interactions and regulation of the transporter, to explore 5-HT contributions to antidepressant action, and to assess the impact of SERT-mediated 5-HT contributions to neuropsychiatric disorders. Here we review three examples from our recent studies where genetic changes in SERT, identified or engineered, have led to new models, findings, and theories that cast light on new dimensions of 5-HT action in the CNS and periphery. First, we review our work to identify specific residues through which SERT recognizes antagonists, and the conversion of this knowledge to the creation of mice lacking high-affinity antidepressant and cocaine sensitivity. Second, we discuss our studies of functional coding variation in SERT that exists in commonly used strains of inbred mice, and how this variation is beginning to reveal novel 5-HT-associated phenotypes. Third, we review our identification and functional characterization of multiple, hyperactive SERT coding variants in subjects with autism. Each of these activities has driven the development of new model systems that can be further exploited to understand the contribution of 5-HT signaling to risk for neuropsychiatric disorders and their treatment.

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

“…Sutcliffe et al (2005) identified five coding variants in subjects diagnosed with ASD. A common finding with these variants is a constitutive increase in 5-HT uptake activity when expressed in HeLa cells Ye and Blakely, 2011). Moreover, for several of these variants, their activity cannot be further increased by p38 MAPK activation , suggesting these variants may be constitutively poised in the state normally produced after p38 MAPK activation.…”

Drosophila melanogaster as a genetic model system to study neurotransmitter transporters

“…To our knowledge, only one mouse model containing a risk allele in hSERT for Attention Deficit Hyperactive Disorder (ADHD) has been generated (Veenstra-VanderWeele et al, 2012). The phenotypic effects of other possible risk alleles in SERT are not known (Ye and Blakely, 2011) and might be explored in the fly.…”

“…We anticipate that similar studies will be very useful to explore the consequences of other risk alleles such as those in SERT linked to autism. To date only one of the SERT mutants has been tested in mice (Ye and Blakely, 2011; Veenstra-VanderWeele et al, 2012). Generating mutant lines in flies or worms may be used for detailed mechanistic studies, or alternatively, large panels of potentially relevant polymorphisms may be screened in model invertebrates to determine which ones should be studied in more detail in mammals.…”

Cocaine modulates mammalian circadian clock timing by decreasing serotonin transport in the SCN

“…Here we explored this hypothesis using recently developed transgenic mice (SERT Met172 ) that express a SERT protein bearing the amino acid substitution, Ile172Met (Thompson et al, 2011;Ye and Blakely, 2011). The substitution yields normal SERT protein expression and paroxetine-sensitive, 5-HT reuptake in vitro and in vivo .…”

“…The substitution yields normal SERT protein expression and paroxetine-sensitive, 5-HT reuptake in vitro and in vivo . However, the alteration leads to a more than 50 fold reduction in cocaine sensitivity for 5-HT reuptake blockade (Thompson et al, 2011;Ye and Blakely, 2011). Here, we use the SERT Met172 mice to demonstrate a critical role of SERT reuptake blockade in the phase shifting properties of cocaine, findings that underscore a key contribution of 5-HT signaling to the plasticities that arise in the context of drug addiction.…”