Causal Mechanisms of Monoamine Transporter Phosphorylation

Monoamine transporters are essential proteins located at presynaptic terminals that play a crucial role in regulating neurotransmission of serotonin, dopamine, and norepinephrine by rapid reuptake of released amines from the synapse. Clinically used antidepressants and widely abused psychostimulants exhibit a high affinity for amine transporters. Function and expression of biogenic amine transporter are altered in subjects suffering from psychiatric diseases such as depression and in psychostimulant use disorder. Therefore, proper functional regulation of monoamine transporters is critical in maintaining normal amine homeostasis. Monoamine transporters possess several potential phosphorylation sites/motifs and exist in a phosphorylated state. Various cellular protein kinases and phosphatases are known to regulate the phosphorylation dynamics of amine transporters, which in turn influences subcellular expression and trafficking, microdomain-specific protein-protein interactions, transporter protein degradation, and overall transport capacity. Dysfunctional amine transporter function, phosphorylation, and association with interacting proteins are evident in neuropsychiatric disease states, including psychostimulant use disorder. However, the neurobiological consequences of in vivo amine transporter phosphorylation and its regulation remain unclear. Recent studies utilizing intact animal models are beginning to connect these molecular mechanisms with observed animal behaviors. This review summarizes current knowledge on the causal role of amine transporter phosphorylation in regulating amine transport and its relevance to animal behavior. Further understanding of phosphorylation-dependent molecular mechanisms governing amine transporter regulation potentially identifies regulatory motif(s) as potential therapeutic targets for treating neuropsychiatric disorders.