Cocaine Regulation of Norepinephrine Transporter
Principal Investigator: LANKUPALLE JAYANTHI
Abstract: The catecholamine, norepinephrine (NE) governs various physiologic processes from vasoconstriction and heart rate to attention and motivation. NE signaling is tightly controlled by a diverse set of macromolecules including biosynthetic enzymes, secretory proteins, ion channels, pre- and post synaptic receptors and NE transporters (NETs). NE signaling is terminated primarily by active reuptake of the catecholamine via cocaine- and amphetamine-sensitive norepinephrine transporters (NETs). Various biologic stimuli are known to regulate NE signaling, and alterations in NE signaling including NE clearance and NET density are observed in cardiovascular diseases and brain disorders. The triggers and molecular mechanisms of transporter regulation are important in the control of extracellular NE concentrations and hence NE signaling. NETs are also expressed in the placenta. This raises the possibility that the established medical complications associated with the maternal use of psychostimulant drugs may arise in part from blocking placental NET. Primary cell cultures offer the facility of in vitro experimentation combined with the verisimilitude of a native cell system to study the molecular mechanisms of transporter regulation a step closer to in vivo animal models. To explore the effect of psychostimulants on NET regulatory pathways, we have developed primary cultures of placental trophoblasts that express endogenous NETs. Using trophoblast cell cultures, we show that NET function and expression are regulated by 1) cocaine treatment, 2) receptor modulation, and 3) kinase(s) activation. Together, these preliminary findings support the proposed experiments to test a specific hypothesis that cocaine regulates NET function and expression via altered cellular mechanisms that result from cocaine effects on NET and/or other cellular targets. The studies proposed in this application will identify the mechanisms of cocaine's action in regulating the function and expression of native NET. Results from these studies will provide valuable scientific insights to our understanding of the role of drugs of abuse in regulating NET function and expression.
Funding Period: 2004-08-01 - 2007-07-31
more information: NIH RePORT
- Evidence for biphasic effects of protein kinase C on serotonin transporter function, endocytosis, and phosphorylationLankupalle D Jayanthi
Department of Physiology and Neuroscience, Medical University of South Carolina, 173 Ashley Ave, BSB 403, Charleston, SC 29425, USA
Mol Pharmacol 67:2077-87. 2005....
- Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressantsLankupalle D Jayanthi
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
AAPS J 7:E728-38. 2005..The review also discusses the possible role of psychostimulants and antidepressants in influencing monoamine transport regulation...
- Phosphorylation of the norepinephrine transporter at threonine 258 and serine 259 is linked to protein kinase C-mediated transporter internalizationLankupalle D Jayanthi
Department of Neurosciences, Division of Neuroscience Research, Medical University of South Carolina, Charleston, South Carolina 29425, USA
J Biol Chem 281:23326-40. 2006..These results suggest that Thr-258 and Ser-259 serve as a PKC-specific phospho-acceptor site and that phosphorylation of this motif is linked to PKC-induced NET internalization...
- Dysregulation of dopamine transporter trafficking and function after abstinence from cocaine self-administration in rats: evidence for differential regulation in caudate putamen and nucleus accumbensDevadoss J Samuvel
Division of Neuroscience Research, Department of Neurosciences, Medical University of South Carolina, 173 Ashley Ave, BSB 403, Charleston, SC 29425, USA
J Pharmacol Exp Ther 325:293-301. 2008....
- Altered dopamine transporter function and phosphorylation following chronic cocaine self-administration and extinction in ratsSammanda Ramamoorthy
Department of Neurosciences, Division of Neuroscience Research, Medical University of South Carolina, Charleston, SC 29425, USA
Biochem Biophys Res Commun 391:1517-21. 2010..Such changes may be related to habitual patterns of cocaine-seeking observed during relapse...