Sammanda Ramamoorthy, Ph.D.
Department: Department of Pharmacology and Toxicology
Phone: (804) 828-8407
Fax: (804) 827-0377
Robert Blackwell Smith Building, Room 758A
410 North Clay Street
Richmond, Virginia 23298
- University of Madras, India
The monoamine transporters mediate the reuptake of released amines from the synapse; thus, the activity of amine transporters is crucial in regulating aminergic neurotransmission. Studies in Dr. Ramamoorthy's laboratory are aimed at understanding the contribution of neurotransmitter transporters in the CNS function, and more specifically, directed toward understanding the role of monoamines such as dopamine, serotonin, and norepinephrine transporters (DAT, SERT, and NET) in normal neurotransmission and relevance to mental illness, drug abuse, aging and neurodegenerative diseases. Medications for treating depression, ADHD, OCD, and other psychiatric disorders exhibit high affinity for these amine transporters. Moreover, amine transporters are molecular targets for psychostimulants/addictive drugs, including cocaine, amphetamines, MDMA (ecstasy), and bath salts. Since the cloning of the human serotonin transporter in 1993, the primary goal of the laboratory has been to understand the molecular basis of transporter regulation. By combining molecular, immunological, and biochemical approaches, continuing studies in the laboratory seek to identify receptors and downstream signaling cascades and dissect cis/trans-signaling pathways that participate in the dynamic process of transporter regulatory pathways in more detail. For example, transporter phosphorylation, trafficking, protein-protein interactions, and stability are studied at the level of transcriptomics, interactomics, proteomics, phosphoproteomics, and lipidomics.
While probing the regulatory mechanisms of amine transporters with increasingly higher resolution, our current efforts are focused on answering (i) is the scientific knowledge gained in in-vitro model systems similar and applicable to native systems? (ii) how to translate this knowledge into complex behaviors at the system level? and (iii) are the dysfunctions in regulatory modules causative factors in altered behavior and brain pathophysiology? Our laboratory approaches these unanswered questions in a multi-faceted way involving neurocircuitry at the molecular, biochemical, neurochemical, behavioral, and systems level integrated pharmacology using both sexes of animal models of addiction, depression, memory, cognitive dysfunction, and aging. Wide array of cutting-edge techniques are employed in Dr. Ramamoorthy’s laboratory conjoining with collaborators, including the generation of novel knock-in mouse models using CRISPR/Cas9 technology, a battery of behavioral assays; neuron-projection specific viral mediated minigene expression; DREADD-mediated manipulations of neuronal activity during behavioral assays; biochemistry; neurochemistry; in vivo fiber photometry; microdialysis; brain slice and in-vivo fast-scan cyclic voltammetry; and in vivo high-speed chronoamperometry.
Our continued effort using a multidisciplinary approach will provide new insights into the causal link between monoamine transporter regulations via phosphorylation and neuro signaling basis for behaviors and how compromised transporter phosphorylation can mediate a switch to a maladaptive set of ensembled behaviors related to neuropsychiatric conditions and substance-use-disorder.
Dr. Ramamoorthy’s laboratory is not only dedicated to helping answer questions in the neurobiology of monoamine transporters but also committed to training students, fellows, and laboratory personnel with new techniques and scientific principles and questions with the hope to motivate and inspire students, fellows, and colleagues.
Complete List of Published Work in My PubMed Bibliography: H-index = 48, i10-index = 77
Ragu Varman D, Jayanthi LD, Ramamoorthy S. Kappa Opioid Receptor Mediated Differential Regulation of Serotonin and Dopamine Transporters in Mood and Substance Use Disorder. Handb Exp Pharmacol. 2022;271:97-112. doi: 10.1007/164_2021_499. PubMed PMID: 34136961.
Ragu Varman D, Subler MA, Windle JJ, Jayanthi LD, Ramamoorthy S. Novelty-induced hyperactivity and suppressed cocaine induced locomotor activation in mice lacking threonine 53 phosphorylation of dopamine transporter. Behav Brain Res. 2021 Jun 25;408:113267. doi: 10.1016/j.bbr.2021.113267. Epub 2021 Mar 29. PubMed PMID: 33794225; PubMed Central PMCID: PMC8117066.
Meinke C, Quinlan MA, Paffenroth KC, Harrison FE, Fenollar-Ferrer C, Katamish RM, Stillman I, Ramamoorthy S, Blakely RD.Serotonin Transporter Ala276 Mouse: Novel Model to Assess the Neurochemical and Behavioral Impact of Thr276 Phosphorylation In Vivo. Neurochem Res. 2021 Apr 8;. doi: 10.1007/s11064-021-03299-w. [Epub ahead of print] PubMed PMID: 33830406.
Ragu Varman D, Jayanthi LD, Ramamoorthy S. Glycogen synthase kinase-3ß supports serotonin transporter function and trafficking in a phosphorylation-dependent manner. J Neurochem. 2021 Feb;156(4):445-464. doi: 10.1111/jnc.15152. Epub 2020 Sep 7. PubMed PMID: 32797733; PubMed Central PMCID: PMC7882002.
Annamalai B, Ragu Varman D, Horton RE, Daws LC, Jayanthi LD, Ramamoorthy S. Histamine Receptors Regulate the Activity, Surface Expression, and Phosphorylation of Serotonin Transporters. ACS Chem Neurosci. 2020 Feb 5;11(3):466-476. doi: 10.1021/acschemneuro.9b00664. Epub 2020 Jan 22. PubMed PMID: 31916747; PubMed Central PMCID: PMC7004881.
Sundaramurthy S, Annamalai B, Samuvel DJ, Shippenberg TS, Jayanthi LD, Ramamoorthy S. Modulation of serotonin transporter function by kappa-opioid receptor ligands. Neuropharmacology. 2017 Feb;113(Pt A):281-292. doi: 10.1016/j.neuropharm.2016.10.011. Epub 2016 Oct 12. PubMed PMID: 27743931; PubMed Central PMCID: PMC5148672.
Mannangatti P, Ramamoorthy S, Jayanthi LD. Interference of norepinephrine transporter trafficking motif attenuates amphetamine-induced locomotor hyperactivity and conditioned place preference. Neuropharmacology. 2018 Jan;128:132-141. doi: 10.1016/j.neuropharm.2017.10.005. Epub 2017 Oct 4. PubMed PMID: 28986281; PubMed Central PMCID: PMC5714664.
Rajamanickam J, Annamalai B, Rahbek-Clemmensen T, Sundaramurthy S, Gether U, Jayanthi LD, Ramamoorthy S. Akt-mediated regulation of antidepressant-sensitive serotonin transporter function, cell-surface expression and phosphorylation. Biochem J. 2015 May 15;468(1):177-90. doi: 10.1042/BJ20140826. PubMed PMID: 25761794.
Mannangatti P, Arapulisamy O, Shippenberg TS, Ramamoorthy S, Jayanthi LD. Cocaine up-regulation of the norepinephrine transporter requires threonine 30 phosphorylation by p38 mitogen-activated protein kinase. J Biol Chem.2011 Jun 10;286(23):20239-50. doi: 10.1074/jbc.M111.226811. Epub 2011 Apr 15. PubMed PMID: 21498515; PubMed Central PMCID: PMC3121486.
Ramamoorthy S, Shippenberg TS, Jayanthi LD. Regulation of monoamine transporters: Role of transporter phosphorylation. Pharmacol Ther. 2011 Feb;129(2):220-38. doi: 10.1016/j.pharmthera.2010.09.009. Epub 2010 Oct 15. Review. PubMed PMID: 20951731; PubMed Central PMCID: PMC3031138.
Ramamoorthy S, Samuvel DJ, Buck ER, Rudnick G, Jayanthi LD. Phosphorylation of threonine residue 276 is required for acute regulation of serotonin transporter by cyclic GMP. J Biol Chem. 2007 Apr 20;282(16):11639-47. doi: 10.1074/jbc.M611353200. Epub 2007 Feb 19. PubMed PMID: 17310063.
Ramamoorthy S, Blakely RD. Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science. 1999 Jul 30;285(5428):763-6. doi: 10.1126/science.285.5428.763. PubMed PMID: 10427004.
Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD. Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2542-6. doi: 10.1073/pnas.90.6.2542. PubMed PMID: 7681602; PubMed Central PMCID: PMC46124.