Department of Neuroscience
Lankupalle Jayanthi, Ph.D.
BSc (BS), Chemistry, Physics and Zoology, 1980-1983, University of Madras, Madras, India
MSc (MS), Biochemistry, 1983-1985, Sri Venkateswara University, Tirupati, India
Ph.D., Biochemistry, 1986-1992, Christian Medical College Hospital, Vellore, India
Recent studies showed altered response to second messenger and/or kinase-mediated regulations in human variants of monoamine transporters identified in mental disorders and other disease phenotypes. These findings underscore the significance of transporter phosphorylation and regulation in normal physiology and pathophysiology. In addition, cocaine and other psychostimulants target monoamine transporters and this action is well recognized as a primary contributor in the addictive properties of these drugs. My research program is focused on understanding how endogenous mediators and drugs of abuse alter norepinephrine transporter (NET) function both in the CNS and periphery. Recently, we have documented the role of lipid rafts in NET trafficking. Very recent findings identified a trafficking motif involved in NET endocytosis and phosphorylation, and demonstrated the involvement of a physiologically relevant endogenous signals (neurokinins) in NET regulation. Studies have shown a relationship between NK1R and noradrenergic system in the CNS, and hence the regulation of NET by NK1R has several physiological implications including a critical role in depression and other mental disorders. In peripheral tissues like placenta, excessive placental secretion of neurokinins has been linked to pre-eclampsia, and hence a close functional relationship might exist between neurokinin-receptor activation and placental NE transport in the maintenance of a normal pregnancy.
Fig. 1: An Overview of Mechanisms and signaling Molecules Involved in NET Phosphorylation and Regulation: Signals linked to endogenous mediators regulate NET phosphorylation and interaction with associated proteins in the rafts, and establish transporter distribution and function. Lipid raft microdomains act as morphological “conveners” of signal transduction by placing various signaling molecules like receptors, kinases and transporter-interacting proteins (syntaxin 1A, PP2Ac, PICK 1) near the vicinity of NET or vice verse and “guide” the targeting of NET to lipid rafts. Phosphorylation of “motif(s)/site(s)” within the transporter may foster protein-protein interactions and transporter redistribution and endocytosis. In addition, NE transport activity influences transporter phosphorylation and interaction with associated proteins dictating NET distribution and internalization in an activity-dependent manner. The functional relevance, signals and the mechanisms mediating raft-specific redistribution of NET are under investigation in Dr. Jayanthi’s laboratory.
Another goal is to understand the mechanisms involved in the functional regulation of monoamine tarnsporters contributing to amine transporter dysfunctions in drug addiction. Figure 2 below shows differential regulation of NET by psychostimulant drugs. Currently, investigations are focused on understanding the implications of in vivo maternal exposure to environmental insults like psychostimulant abuse as well as stress, inflammation and antidepressant treatments on the functional expression of monoamine transporters SERT, NET and DAT in maternal systems and fetal brain, and to relate to behavioral alterations in the developing offspring.
Areas of research include transporter regulation by protein kinases, phosphatases, drugs of abuse and antidepressant treatments, transporter trafficking and signal transduction. Protein, cellular, molecular biological, and immunological methods are being employed.
Fig. 2: Cocaine and Amphetamine Differentially Regulate NET Expression
Recent publications: *Corresponding author
*Jayanthi, L.D., Samuvel, J.D., and Ramamoorthy, S. (2004) Regulated Internalization and Phosphorylation of the Native Norepinephrine Transporter in Response to Phorbol Esters. Evidence for localization in lipid rafts and lipid raft-mediated internalization. Journal of Biological Chemistry. 279: 19315-19326.
Samuvel, D.J., Jayanthi, L.D., and Ramamoorthy, S. (2005) A Role for p38 MAP Kinase in the Regulation of the Serotonin Transporter: Evidence for Distinct Cellular Mechanisms Involved in Transporter Surface Expression. Journal of Neuroscience. 25: 29-41
Jayanthi, L.D., Samuvel, D.J., Blakely, R.D., and Ramamoorthy, S. (2005) Regulation of Cocaine and Antidepressant-sensitive Native Serotonin Transporters: Evidence for Biphasic Effects of Protein Kinase C on Serotonin Transporter Function, Endocytosis, and Phosphorylation. Molecular Pharmacology. 67: 2077-2087
*Jayanthi, L.D., Annamalai, B., Samuvel, D.J., and Ramamoorthy, S. (2006) Phosphorylation of the Norepinephrine Transporter at Threonine 258 and Serine 259 is linked to Protein Kinase C-Mediated Transporter Internalization. Journal of Biological Chemistry (in press).
*Jayanthi, L.D., and Ramamoorthy S. (2006). Regulation of monoamine transporters: Influence of psychostimulants and therapeutic antidepressants. American Association of Pharmaceutical Scientists (AAPS) Journal. 7: E728-E738.