Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

Abstract

Modulation of neurotransmission by the monoamines dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is critical for normal nervous system function. Precise temporal and spatial control of this signaling in mediated in large part by the actions of monoamine transporters (DAT, NET, and SERT, respectively). These transporters act to recapture their respective neurotransmitters after release, and disruption of clearance and reuptake has significant effects on physiology and behavior and has been linked to a number of neuropsychiatric disorders. To ensure adequate and dynamic control of these transporters, multiple modes of control have evolved to regulate their activity and trafficking. Central to many of these modes of control are the actions of protein kinases, whose actions can be direct or indirectly mediated by kinase-modulated protein interactions. Here, we summarize the current state of our understanding of how protein kinases regulate monoamine transporters through changes in activity, trafficking, phosphorylation state, and interacting partners. We highlight genetic, biochemical, and pharmacological evidence for kinase-linked control of DAT, NET, and SERT and, where applicable, provide evidence for endogenous activators of these pathways. We hope our discussion can lead to a more nuanced and integrated understanding of how neurotransmitter transporters are controlled and may contribute to disorders that feature perturbed monoamine signaling, with an ultimate goal of developing better therapeutic strategies.

Fig. 1.

Potential phosphorylation sites in DAT. Model shows intracellular serine (yellow), threonine (green), and tyrosine (cyan) residues in the human DAT protein. Residue names in red are supported by the literature to be phosphorylated based on in vitro kinase assays with purified proteins, mutagenesis studies, phospho-specific antibodies, and/or mass spectrometry analysis (see text for discussion). Sites that show species variation between human, mouse, and rat are marked with an asterisk (*).

Fig. 2.

Potential phosphorylation sites in NET. Model shows intracellular serine (yellow), threonine (green), and tyrosine (cyan) residues in the human NET protein. Residue names in red are supported by the literature to be phosphorylated based on in vitro kinase assays with purified proteins, mutagenesis studies, phospho-specific antibodies, and/or mass spectrometry analysis (see text for discussion). Sites that show species variation between human, mouse, and rat are marked with an asterisk (*).

Fig. 3.

Potential phosphorylation sites in SERT. Model shows intracellular serine (yellow), threonine (green), and tyrosine (cyan) residues in the human SERT protein. Residue names in red are supported by the literature to be phosphorylated based on in vitro kinase assays with purified proteins, mutagenesis studies, phospho-specific antibodies, and/or mass spectrometry analysis (see text for discussion). Sites that show species variation between human, mouse, and rat are marked with an asterisk (*).