REGULATED PHOSPHORYLATION AND TRAFFICKING OF ANTIDEPRESSANT-SENSITIVESEROTONIN TRANSPORTER PROTEINS

Presynaptic serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) mediate antidepressant-sensitive clearance of 5-HT following release. Although we have been aware for decades that SERT-mediated 5-HT clear ance can be modulated by exogenous agents including serotonin-selectiv e reuptake inhibitors, amphetamines, and cocaine, we have had little r eason to speculate that SERT activity was actively controlled through endogenous pathways. Recent studies indicate that SERTs are likely to be trafficked to specific plasma membrane subdomains to achieve locali zed clearance of 5-HT, and that the number of SERTs resident in the pl asma membrane is controlled through kinase- and phosphatase-linked pat hways. In particular, roles for protein kinase C and phosphatase 2A be come apparent through studies with enzyme activators and inhibitors in SERT-transfected cells, where SERT proteins are rapidly phosphorylate d in parallel with transporter redistribution and loss of functional u ptake capacity. Based on our findings, and the studies of others in na tive tissues and transfected cells, we propose a model whereby SERTs a re organized in a macromolecular complex in the plasma membrane that m ay serve to locate reuptake activity near release sites. Although many elements of this model remain hypothetical, our findings suggest a mu ch more dynamic picture of transporter-mediated 5-HT reuptake than typ ically described and suggest opportunities both for the development of new SERT regulatory agents and for the identification of regulatory p athways that may be compromised in mental illness. (C) 1998 Society of Biological Psychiatry.