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Evidence for biphasic effects of protein kinase C on serotonin transporter function, endocytosis, and phosphorylation.
Jayanthi LD, Samuvel DJ, Blakely RD, Ramamoorthy S
(2005) Mol Pharmacol 67: 2077-87
MeSH Terms: Animals, Dose-Response Relationship, Drug, Endocytosis, Membrane Glycoproteins, Membrane Transport Modulators, Membrane Transport Proteins, Nerve Tissue Proteins, Phorbols, Phosphorylation, Protein Kinase C, Rats, Serotonin, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added July 10, 2013
The serotonin transporter (SERT) regulates 5-hydroxytryptamine (serotonin) (5-HT) neurotransmission and is a high-affinity target for antidepressants and psychostimulants. In the present study, we investigated the mechanisms that contribute to a previously unidentified biphasic regulation of endogenous SERTs expressed in the platelets. Treatment of rat platelets with beta-phorbol 12-myristate 13-acetate (PMA) for 5 min or less resulted in a rapid inhibition of SERT involving changes in intrinsic activity of the transporter (increased K(m) and decreased V(max)). beta-PMA treatment for 30 min or more produced a sustained inhibition of SERT with a decrease only in the V(max). Whereas inhibition of SERT activity was detected from 1 to 45 min after phorbol ester addition, the decrease in surface SERT required at least 30 min of phorbol ester incubation. Increased endocytosis of SERT accounted for the decrease in surface SERT at the later point. Protein kinase C (PKC)-mediated phosphorylation of SERT occurs on the plasma membrane during the initial phase of rapid transporter inhibition, and later, the phosphorylated SERT enters the intracellular pool. beta-PMA-induced phosphorylation of SERT occurs initially on serine residues(s) and then on threonine residue(s). The initial serine phosphorylation corresponded to the first phase of rapid inhibition mediated by changes in intrinsic activity and/or silencing of SERT. The later phosphorylation on threonine residue(s) corresponded to the later phase of sustained inhibition mediated by an enhanced endocytosis of SERT. Together, these data reveal that in platelets, SERT function is regulated by PKC in a biphasic manner involving both trafficking-dependent and independent mechanisms and that these two events occur at distinct phases of transporter phosphorylation.
1 Communities
1 Members
0 Resources
13 MeSH Terms
Activation of PKC disrupts presynaptic inhibition by group II and group III metabotropic glutamate receptors and uncouples the receptor from GTP-binding proteins.
Macek TA, Schaffhauser H, Conn PJ
(1999) Ann N Y Acad Sci 868: 554-7
MeSH Terms: Adenosine, Animals, Dihydropyridines, Enzyme Activation, GTP-Binding Proteins, Guanosine 5'-O-(3-Thiotriphosphate), Hippocampus, Phorbol 12,13-Dibutyrate, Phorbols, Propionates, Protein Kinase C, Receptor, Adenosine A3, Receptors, Metabotropic Glutamate, Receptors, Purinergic P1, Synaptic Transmission
Added February 19, 2015
0 Communities
1 Members
0 Resources
15 MeSH Terms