Role of Phosphorylation of Serotonin and Norepinephrine Transporters in Animal Behavior: Relevance to Neuropsychiatric Disorders.

Serotonin and norepinephrine transporters (SERT and NET), located on the presynaptic terminals, regulate serotonergic (5-HT) and noradrenergic (NE) neurotransmission by rapid reuptake of released amines from the synapse. Clinically used antidepressants and highly abused psychostimulants have high affinity for these transporters. The function and expression of SERT and NET are altered in mood disorders and psychostimulant use. Therefore, appropriate functional regulation of SERT and NET is important in maintaining normal homeostasis of 5-HT and NE signaling. Both SERT and NET possess kinase-specific phospho-sites/motifs and exist in phosphorylated state. Several cellular protein kinases and phosphatases regulate the dynamics of phosphorylation of SERT and NET, which in turn determine the subcellular expression and trafficking, microdomain-specific protein-protein interactionsprotein-protein interactions, transporter protein degradation and ultimately transport capacity. Dysregulations in the dynamics of SERT and NET phosphorylation and their impact on functional regulation might contribute to neuropsychiatric disorders. However, the neurobiological consequences and behavioral outcome of SERT and NET phosphorylation in vivo are not fully understood. Studies using intact animal models that directly link the phosphorylation of SERT and NET to regulatory molecular mechanisms and animal behavior are just beginning to emerge. This review summarizes our understanding of the role of phosphorylation-dependent regulation of SERT and NET in animal behaviors relevant to mood and psychostimulant use disorders. Understanding of phosphorylation-dependent molecular mechanisms of SERT and NET regulation is pivotal to identifying potential candidate mechanisms as therapeutic targets in the treatment of neuropsychiatric disorders.