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Satinder Kaur Singh, PhD

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Associate Professor Adjunct
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About

Titles

Associate Professor Adjunct

Biography

Satinder was born in Boston, MA and moved, as a teenager, to Minneapolis, MN, with her family. She received her doctoral degree in Biochemistry & Molecular Biophysics from the University of Minnesota – Twin Cities, supported by an HHMI Predoctoral Fellowship. She has had a long-standing interest in the molecular mechanisms of neuropsychiatric disease, particularly in the role that the biogenic amines play. As a postdoctoral fellow, she combined her knowledge of neuropsychopharmacology and enzymology with X-ray crystallography to develop molecular models of transport and inhibition for LeuT, a bacterial orthologue of neurotransmitter sodium symporters (NSS). At Yale, Satinder has been concentrating on eukaryotic NSS members, specifically those that transport the biogenic amines serotonin (SERT) and dopamine (DAT).

Appointments

Other Departments & Organizations

Education & Training

Postdoctoral Fellow
Oregon Health and Science University (2008)
Postdoctoral Fellow
Columbia University (2005)
PhD
University of Minnesota, Biochemistry, Molecular Biology, & Biophysics (2002)
BS
University of Minnesota, Biochemistry (1995)

Research

Overview

Signal transduction in the human brain is a complex, highly regulated process. The transmission and regulation of nerve impulses among neurons are mediated by a number of proteins, including ion channels, G-protein coupled receptors, protein kinases, protein phosphatases, and neurotransmitter transporters, to name only a few. Significantly, many of these proteins are the target of potent psychoactive substances and antiepileptic drugs. Furthermore, their dysfunction has been implicated in the development of multiple debilitating neuropsychiatric and neurological diseases such as obsessive-compulsive disorder (OCD), autism, depression, schizophrenia, Parkinson’s disease, Tourette’s syndrome, and epilepsy.

Little is known about the molecular basis of these illnesses, but their underlying neural circuitry is gradually being revealed by a combination of functional neuroimaging, genome-wide association, transgenics, optogenetics, and neuropsychopharmacology. For instance, in OCD, an illness marked by intense intrusive thoughts and ritualistic behavior, hyperactivity in the circuit connecting the orbitofrontal cortex, cingulate gyrus, striatum, and caudate nucleus (the orbitofrontal corticostriatal circuit) has been correlated with symptom severity (Graybiel & Rauch, 2000). These brain regions receive extensive input from serotonergic and dopaminergic neurons, and both serotonin and dopamine have been implicated in the pathogenesis of OCD. Indeed, some of more effective treatments for OCD target the serotonin transporter (SERT) and include the tricyclic antidepressant (TCA) clomipramine and a few of the selective serotonin reuptake inhibitors (SSRIs). Although prescribed less frequently, atypical antipsychotics (dopamine D2 / serotonin 5HT2a receptor antagonists) are used as augmenting agents in treatment refractory cases.

My lab seeks to ascertain how signaling proteins in these neural circuits function at the atomic level, how disease-associated polymorphisms disrupt activity and how therapeutic and illicit compounds exert their effects. To achieve our objectives, we employ a broad range of complementary biochemical and biophysical tools such as X-ray crystallography, steady-state flux/binding kinetics, nanodisc technology, and hydrogen-deuterium exchange mass spectrometry (HDX-MS).

We are presently focusing our efforts on the plasma membrane neurotransmitter transporters for the biogenic amines serotonin (SERT) and dopamine (DAT). These molecular machines work by coupling preexisting sodium and chloride electrochemical gradients to the energetically unfavorable movement of the respective neurotransmitter from the synaptic cleft back into neuronal and glial cytoplasms. Because they function primarily after neurotransmitters have been released from the presynaptic neuron and activated postsynaptic receptors, these integral membrane proteins play a crucial role in terminating synaptic transmission and thus in shaping the duration and magnitude of synaptic signaling.


We are examining the substrate/ion specificity of these symporters and the dynamic conformational changes that occur during the transport cycle. We are also attempting to pinpoint antagonist binding sites and to elucidate the atomic mechanism by which psychoactive substances such as TCAs, SSRIs, cocaine, and amphetamine, modulate transport. Our ultimate goal is to help pave the road toward rational, structure-based drug design efforts and to shed light on the molecular underpinnings of disease-associated polymorphisms and drug resistance.

Medical Subject Headings (MeSH)

Antidepressive Agents; Antipsychotic Agents; Biogenic Monoamines; Depression; Dopamine; Epilepsy; gamma-Aminobutyric Acid; Glycine; Lipid Bilayers; Neurobiology; Neuropharmacology; Neuropsychiatry; Neurotransmitter Transport Proteins; Obsessive-Compulsive Disorder; Protein Structure, Tertiary; Schizophrenia; Serotonin; Synaptic Vesicles; X-Ray Diffraction

Research at a Glance

Publications Timeline

A big-picture view of Satinder Kaur Singh's research output by year.

Publications

2019

2018

2017

2016

2015

2014

Academic Achievements & Community Involvement

  • honor

    NARSAD Independent Investigator Award

  • honor

    Sloan Research Fellowship Award

  • honor

    Goodman & Gilman Yale Scholar Award

  • honor

    NIH/NIMH K99/R00 "Pathway to Independence Award"

  • honor

    NIH/NINDS Individual NRSA Postdoctoral Fellowship

Get In Touch

Contacts

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Mailing Address

Cellular & Molecular Physiology

211 East Ohio Street, Apt 1901

Chicago, IL 60611

United States

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