Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin 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 clearance can be modulated by exogenous agents including serotonin-selective reuptake inhibitors, amphetamines, and cocaine, we have had little reason 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 localized clearance of 5-HT, and that the number of SERTs resident in the plasma membrane is controlled through kinase- and phosphatase-linked pathways. In particular, roles for protein kinase C and phosphatase 2A become apparent through studies with enzyme activators and inhibitors in SERT-transfected cells, where SERT proteins are rapidly phosphorylated in parallel with transporter redistribution and loss of functional uptake capacity. Based on our findings, and the studies of others in native tissues and transfected cells, we propose a model whereby SERTs are organized in a macromolecular complex in the plasma membrane that may serve to locate reuptake activity near release sites. Although many elements of this model remain hypothetical, our findings suggest a much more dynamic picture of transporter-mediated 5-HT reuptake than typically described and suggest opportunities both for the development of new SERT regulatory agents and for the identification of regulatory pathways that may be compromised in mental illness.
Department of Pharmacology and Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6600, USA.
R D
RD
Blakely
S
S
Ramamoorthy
S
S
Schroeter
Y
Y
Qian
S
S
Apparsundaram
A
A
Galli
L J
LJ
DeFelice
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D003866:Depressive Disorder / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D012701:Serotonin / Q000097:blood*; D050486:Serotonin Plasma Membrane Transport Proteins
D000928:Antidepressive Agents; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D011493:Protein Kinase C; D010744:Phosphoric Monoester Hydrolases