Cellular & Integrative Physiology Seminar – Lankupalle Jayanthi, PhD

Lankupalle Jayanthi, PhD
Associate Professor
Dept. of Pharmacology and Toxicology
Virginia Common Wealth University

Title: “The molecular codes: Catecholamine transporters’ phospho-sites in the actions of psychostimulants”

Summary: Chronic drug abuse and addiction to psychostimulants, cocaine and amphetamine (AMPH) involve many neuroadaptations and there are no effective medications to treat psychostimulant substance-use disorder (SUD), likely because of lack of thorough understanding of the complex neurobiology underlying the disorder. Noradrenergic and dopaminergic neurotransmission in the mesolimbic circuit plays a critical role in SUD. Both cocaine and AMPH inhibit norepinephrine (NE) and dopamine (DA) transporters (NET and DAT) promoting behavioral effects. Both NET and DAT, principal mediators of NE/DA signaling, are regulated by post-translational modifications, such as phosphorylation and protein-protein interactions. However, to date, post-translational modifications have not been a focus of investigation in the SUD field. Our published studies over several years demonstrated that phosphorylation of Thr258/Ser259 motif, a neurokinin 1 receptor (NK1R)-linked PKC site in NET, plays a pivotal role in NET regulation. Our studies also uncovered that phosphorylation of Thr53, a kappa-opioid receptor (KOR)-linked ERK1/2 site in DAT, plays a critical role in DAT regulation. While probing the in vivo regulatory mechanisms of NET and DAT with increasingly higher resolution, we extended these concepts to critical tests of behaviors relevant to neuropsychiatric disorders including psychostimulant SUD. In my talk, I will present our work on the role of T258/S259-dependent NET phosphorylation/regulation and Thr53-dependent DAT phosphorylation/regulation in psychostimulant actions, using our newly developed mouse models lacking Thr258/Ser259 phosphorylation in NET and Thr53 phosphorylation in DAT. We derived evidence to conclude that while Thr258/Ser259-dependent in vivo NET regulation impacts rewarding effects of AMPH, in vivo regulation of DAT-Thr53 phosphorylation impacts KOR-mediated negative affective states that drive cocaine-reward. We believe that phosphorylation of specific phospho-motif in specific transporter protein represents a molecular code in amine signaling regulating animal behavior and such motifs may serve as therapeutic targets.