Slesinger Laboratory
Membrane Excitability & Disease

Research

My long-term objective is to discover new drugs for treating addiction to drugs of abuse and alcohol. Currently, there are few FDA approved drugs for treating these diseases and more are greatly needed. Many of the neurotransmitters in the drug-reward pathway exert their effects by activating G protein-coupled receptors, which, in turn, communicate with specific G proteins and affect down-stream signaling pathways. One of the down-stream targets is the G protein-gated inwardly rectifying potassium (GIRK) channel, which we study in my laboratory. By controlling the membrane excitability of neurons, GIRK channels provide a fundamental source of neuromodulatory inhibition in the brain. My laboratory has been addressing fundamental questions concerning the function of GIRK channels in the brain, taking a broad approach of combining structural biology, biochemistry, electrophysiology and behavior. We have contributed significant work on the mechanism underlying G protein-regulation and gating of GIRK channels, provided evidence for the assembly of GIRK channels in macromolecular signaling complexes, and identified novel proteins that regulate GIRK channels. More recently, we have elucidated the subcellular mechanisms underlying the neuroplastic changes in GIRK channel signaling with drugs of abuse and alcohol.

Contact Us

Slesinger Laboratory
Paul Slesinger, PhD
Lillian and Henry M. Stratton Professor of Neuroscience
Director, Center for Neurotechnology & Behavior

Areas of Research

Molecular studies of GIRK channels and Alcohol

The alcoholic beverages we consume contain ethanol. Alcohol consumptions can lead to dependence, and eventually alcohol use disorder (AUD). Ethanol produces complex effects on the body, primarily through its interactions within the central nervous system. How ethanol alters neuronal circuits in the brain and causes AUD is poorly understood. Unlike drugs of abuse, ethanol produces a wide range of pharmacological effects on the nervous system, ranging from anxiolytic to intoxication, and has a number of different targets in the brain. One of the targets for ethanol is GIRK channels. GIRK channels are G protein-activated potassium channels that control the excitability of neurons. We are investigating the structural mechanism underlying alcohol-dependent activation of GIRK channels and the role of these channels in alcohol-related behaviors. We are taking an innovative approach of using structural biology to guide screening and selection of novel therapeutics, and validating drug effects with ex vivo and in vivo systems. We recently identified and characterized a new GIRK modulator, called GiGA1. We are also using cryoEM to study the structural mechanism underlying activation of GIRK channels and GABA(B) receptors by different ligands.

For topical reviews, see Lüscher and Slesinger (2010) Nat Rev Neurosci & Glaaser and Slesinger (2015) International Review of Neurobiology

Drug addiction and the reward circuit

Psychostimulants, such as methamphetamine and cocaine, are highly addictive, and abused by millions of people. Recent work from our laboratory has established that drug exposure reduces slow inhibition, mediated by GABA(B) receptors that activate GIRK channels. We have delineated two different mechanisms of drug-dependent plasticity in VTA neurons. In GABA neurons, psychostimulant-dependent depression of GABA(B)-GIRK currents involves de-phosphorylation of the GABA(B) R2 receptor via the protein phosphatase PP2a. In DA neurons, psychostimulant-dependent depression of GABA(B)-GIRK currents involves the GIRK3 subunit and an endosomal trafficking protein SNX27. We are currently examining the role of GIRK channels in projection specific VTA neurons using chemogenetics (i.e. DREADDs), and searching for new GIRK regulatory proteins using BioID. To develop new therapeutics for treating addiction, it is essential to elucidate the components of drug-dependent plasticity in the brain and discover novel protein targets in the reward pathway.

For topical review, see Rifkin et al (2017) Trends in Pharmacological Sciences

Monitoring neuromodulator release and action in real-time

As part of the NIH Brain Initiative, our lab is actively involved in developing new innovative neurotechniques for optically dissecting the function of neuromodulators in the brain of awake animals.  We have created cell-based biosensors (CNiFERs) to optically measure the release of neuropeptides in cell-specific and circuit-specific processes in the brain, in collaboration with the Kleinfeld laboratory at the Univ. of California, San Diego. CNiFERs detect nM concentrations of transmitter, have a temporal resolution of seconds, and a spatial resolution of < 100 μm. In collaboration with Qin laboratory at the Univ. of Texas at Dallas, we are developing a technique of photo-releasing peptides and other modulators in the brain with two photon precision.  In combination with CNiFERs, we can begin to understand the diffusion of peptides in the brain.

For topical papers, see Muller et al (2014) Nature MethodsXiong et al (2020) Angew Chem Int Ed

Studies of human diseases using hiPSCs

Excessive alcohol use is one of the top 10 contributors to disability worldwide, and an estimated 16 million Americans meet the criteria for alcohol use disorders (AUD). AUD is heritable (50-60%), polygenic and results from the contributions of genes and environment. We are part of a multi-institution research program, called the Collaborative Studies on the Genetics of Alcoholism (COGA), supported by the National Institute of Alcohol Abuse and Alcoholism (NIAAA).  COGA’s primary goal is to identify the genes that increase or decrease the risk of alcoholism. Our laboratory is using human induced pluripotent stem cell (hiPSC)-based models to study the effect of risk genes on the functional activity of human neurons, to better understand the role of genetics in AUD.

For topical review, see Prytkova et al (2018) Alcohol Clin Exp Res.

Schizophrenia, bipolar disorder and autism are common and debilitating neurodevelopmental disorders that together affect more than 5 million Americans. Despite more than fifty years of research, no cures exist, and the standard of treatment remains unsatisfactory. Heterozygous mutations of neurexin-1 (NRXN1) have been repeatedly associated with schizophrenia (SZ) and autism spectrum disorder (ASD). In collaboration with Dr. Brennand, we are investigating how NRXN1+/- deletions perturb the NRXN1 isoform repertoire and impact neuronal maturation and synaptic function, using experimental manipulations of control and NRXN1+/- patient-derived excitatory and inhibitory neurons.

For topical review, see Fernando et al (2020) Nat Genet.

Publications

2020

Barretto N, Fernando MB, Powell S, Zhang H, Zhang S, Flaherty EK, Ho SM, Slesinger PA, Duan J, Brennand KJ (2020) ASCL1- and DLX2-induced GABAergic interneurons from hiPSC-derived NPCs. J Neurosci Methods. 2020 334:108548. doi: 10.1016/j.jneumeth.2019.108548.


Li X, Terunuma M, Deeb TG, Wiseman X, Pangalos MN, Nairn AC, Moss SJ and Slesinger PA. (2020) Direct interaction of PP2A phosphatase with GABAB receptors alters functional signaling. J Neurosci. 2020 Feb 26. pii: 2654-19. doi: 10.1523/JNEUROSCI.2654-19.2020


Xiong H, Li X, Kang P, Perish J, Neuhaus F, Ploski JE, Kroener S, Ogunyankin MO, Shin JE, Zasadzinski JA, Wang H, Slesinger PA, Zumbuehl A, Qin Z. Near-infrared Light Triggered-release in Deep Brain Regions Using Ultra-photosensitive Nanovesicles. Angew Chem Int Ed Engl. 2020 Mar 2. doi: 10.1002/anie.201915296


Park J, Fu ZJ, Frangaj, Liu J, Mosyak L, Shen T, Slavkovich VN, Ray KM, Cao B, Geng Y, Zuo H, Kou Y, Grassucci R, Chen S, Liu Z, Rice W, Eng E, Huang RK, Soni RK, Kloss B, Yu Z, Potter C, Carragher BO, Slesinger PA, Hendrickson WA, Quick M, Graziano J, Yu H, Fiehn O, Henderson R, Clarke OB, Frank J, Fan QR (2020) Cryo-EM structure of human GABAB G protein-coupled receptor. Nature. 2020 Jun 24. doi: 10.1038/s41586-020-2452-0. PMID: 32581365


Zhao Y, Ung PMU, Zahoranszky-Kohalmi G, Zakharov A, Martinez N, Simeonov A, Glaaser IW, Bantukallu G, Schlessinger A, Marugan JJ, Slesinger PA (2020) Discovery of a G protein-independent activator (GiGA1) of GIRK channels. Cell Rep. 2020 Jun 16;31(11):107770. doi: 10.1016/j.celrep.2020.107770. PMID: 32553165


Mathiharan YK, Glaaser IW, Zhao Y, Robertson MJ, Skiniotis G, Slesinger PA (2020) Structural basis of GIRK2 channel modulation by cholesterol and PIP2. BioRxiv 2020.06.04.134544; doi: https://doi.org/10.1101/2020.06.04.134544

2019

Kircher DM, Lacin ME, Kleinfeld D and Slesinger PA (2019) CNiFERs: cell-based biosensors with nanomolar sensitivity to in vivo changes in neuromodulation. Chapter 2 in Compendium of In Vivo Monitoring in Real-Time Molecular Neuroscience. https://doi.org/10.1142/9789811206238_0002

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Zuo H, Glaaser IW, Zhao Y, Kurinov I, Mosyak L, Wang H, Liu J, Park J, Frangaj A, Sturchler E, Zhou M, McDonald P, Geng Y, Slesinger PA, and Fan QR (2019) Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor. Proc Natl Acad Sci USA 116(17):8370-8379. doi: 10.1073/pnas.1903024116. PMID: 30971491 PMCID: PMC6486783

2018

GIRK currents in VTA dopamine neurons control the sensitivity of mice to cocaine-induced locomotor sensitization
Rifkin RA, Huyghe D, Li X, Parakala M, Aisenberg E, Moss SJ and Slesinger PA (2018). Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):E9479-E9488. doi: 10.1073/pnas.1807788115. Epub 2018 Sep 18. PMID: 30228121


Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells?
Prytkova I, Goate A, Hart RP, Slesinger PA.
Alcohol Clin Exp Res. 2018 Jun 13. doi: 10.1111/acer.13811. [Epub ahead of print] Review.
PMID: 29897633


Gain-of-function KCNJ6 Mutation in a Severe Hyperkinetic Movement Disorder Phenotype.
Horvath GA, Zhao Y, Tarailo-Graovac M, Boelman C, Gill H, Shyr C, Lee J, Blydt-Hansen I, Drögemöller BI, Moreland J, Ross CJ, Wasserman WW, Masotti A, Slesinger PA, van Karnebeek CDM.
Neuroscience. 2018 Aug 1;384:152-164. doi: 10.1016/j.neuroscience.2018.05.031. Epub 2018 May 29.
PMID: 29852244

2017

THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Overview.
Alexander SP, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Buneman OP, Cidlowski JA, Christopoulos A, Davenport AP, Fabbro D, Spedding M, Striessnig J, Davies JA; CGTP Collaborators.
Br J Pharmacol. 2017 Dec;174 Suppl 1:S1-S16. doi: 10.1111/bph.13882.
PMID: 29055037


An Efficient Platform for Astrocyte Differentiation from Human Induced Pluripotent Stem Cells.
Tcw J, Wang M, Pimenova AA, Bowles KR, Hartley BJ, Lacin E, Machlovi SI, Abdelaal R, Karch CM, Phatnani H, Slesinger PA, Zhang B, Goate AM, Brennand KJ.
Stem Cell Reports. 2017 Aug 8;9(2):600-614. doi: 10.1016/j.stemcr.2017.06.018. Epub 2017 Jul 27.
PMID: 28757165


Dynamic role of the tether helix in PIP2-dependent gating of a G protein-gated potassium channel.
Lacin E, Aryal P, Glaaser IW, Bodhinathan K, Tsai E, Marsh N, Tucker SJ, Sansom MSP, Slesinger PA.
J Gen Physiol. 2017 Jul 18. pii: jgp.201711801. doi: 10.1085/jgp.201711801. [Epub ahead of print]
PMID: 28720589


Dual activation of neuronal G protein-gated inwardly rectifying potassium (GIRK) channels by cholesterol and alcohol.
Glaaser IW, Slesinger PA.
Sci Rep. 2017 Jul 4;7(1):4592. doi: 10.1038/s41598-017-04681-x.
PMID: 28676630


G Protein-Gated Potassium Channels: A Link to Drug Addiction.
Rifkin RA, Moss SJ, Slesinger PA.
Trends Pharmacol Sci. 2017 Apr;38(4):378-392. doi: 10.1016/j.tips.2017.01.007. Epub 2017 Feb 7. Review.
PMID: 28188005

2016

Construction of Cell-based Neurotransmitter Fluorescent Engineered Reporters (CNiFERs) for Optical Detection of Neurotransmitters In Vivo.
Lacin E, Muller A, Fernando M, Kleinfeld D, Slesinger PA.
J Vis Exp. 2016 May 12;(111). doi: 10.3791/53290.
PMID: 27214050


A Role for the GIRK3 Subunit in Methamphetamine-Induced Attenuation of GABAB Receptor-Activated GIRK Currents in VTA Dopamine Neurons.
Munoz MB, Padgett CL, Rifkin R, Terunuma M, Wickman K, Contet C, Moss SJ, Slesinger PA.
J Neurosci. 2016 Mar 16;36(11):3106-14. doi: 10.1523/JNEUROSCI.1327-15.2016.
PMID: 26985023


Rapid Ngn2-induction of excitatory neurons from hiPSC-derived neural progenitor cells.
Ho SM, Hartley BJ, Tcw J, Beaumont M, Stafford K, Slesinger PA, Brennand KJ.
Methods. 2016 May 15;101:113-24. doi: 10.1016/j.ymeth.2015.11.019. Epub 2015 Nov 25.
PMID: 26626326


A role for the GIRK3 subunit in methamphetamine-induced attenuation of GABAB receptor-activated GIRK currents in VTA dopamine neurons. Munoz MB, Padgett CL, Rifkin R, Terunuma M, Wickman K, Contet C, Moss SJ and Slesinger PA. (2016) J. Neurosci (in press)


Construction of cell-based neurotransmitter fluorescently engineered reporters (CNiFERs) for optical detection of neurotransmitters in vivo Lacin M, Muller A, Kleinfeld D and Slesinger, PA (2016) Construction of cell-based neurotransmitter fluorescently engineered reporters (CNiFERs) for optical detection of neurotransmitters in vivo. Journal of Visualized Experiments (in press).

2015

Stress and Cocaine Trigger Divergent and Cell Type-Specific Regulation of Synaptic Transmission at Single Spines in Nucleus Accumbens. Khibnik LA, Beaumont M, Doyle M, Heshmati M, Slesinger PA, Nestler EJ, Russo SJ. Biol Psychiatry. 2015 Jun 6. pii: S0006-3223(15)00471-0. doi:


GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol. Herman MA, Sidhu H, Stouffer DG, Kreifeldt M, Le D, Cates-Gatto C, Munoz MB, Roberts AJ, Parsons LH, Roberto M, Wickman K, Slesinger PA, Contet C. Proc Natl Acad Sci USA. 2015 Jun 2;112(22):7091-6. doi: 10.1073/pnas.1416146112.


GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner. Kotecki L, Hearing M, McCall NM, Marron Fernandez de Velasco E, Pravetoni M, Arora D, Victoria NC, Munoz MB, Xia Z, Slesinger PA, Weaver CD, Wickman K. J Neurosci. 2015 May 6;35(18):7131-42. doi: 10.1523/JNEUROSCI.5051-14.2015.


Chromatin landscape defined by repressive histone methylation during oligodendrocyte differentiation. Liu J, Magri L, Zhang F, Marsh NO, Albrecht S, Huynh JL, Kaur J, Kuhlmann T, Zhang W, Slesinger PA, Casaccia P. J Neurosci. 2015 Jan 7;35(1):352-65. doi: 10.1523/JNEUROSCI.2606-14.2015.


Novel mechanism of voltage-gated N-type (Cav2.2) calcium channel inhibition revealed through α-conotoxin Vc1.1 activation of the GABA(B) receptor. Huynh TG, Cuny H, Slesinger PA, Adams DJ. Mol Pharmacol. 2015 Feb;87(2):240-50. doi: 10.1124/mol.114.096156

2014

Cell-based reporters reveal in vivo dynamics of dopamine and norepinephrine release in murine cortex. Muller A, Joseph V, Slesinger PA, Kleinfeld D. Nat Methods. 2014 Dec;11(12):1245-52. doi: 10.1038/nmeth.3151. Epub 2014 Oct 26.


Sorting nexin 27 regulation of G protein-gated inwardly rectifying K⁺ channels attenuates in vivo cocaine response. Munoz MB, Slesinger PA. Neuron. 2014 May 7;82(3):659-69. doi: 10.1016/j.neuron.2014.03.011.


Firing modes of dopamine neurons drive bidirectional GIRK channel plasticity. Lalive AL, Munoz MB, Bellone C, Slesinger PA, Lüscher C, Tan KR. J Neurosci. 2014 Apr 9;34(15):5107-14. doi: 10.1523/JNEUROSCI.5203-13.2014.

2013

Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels. Bodhinathan K, Slesinger PA. Proc Natl Acad Sci USA. 2013 Nov 5;110(45):18309-14. doi: 10.1073/pnas.1311406110.


Ras-association domain of sorting Nexin 27 is critical for regulating expression of GIRK potassium channels. Balana B, Bahima L, Bodhinathan K, Taura JJ, Taylor NM, Nettleton MY, Ciruela F, Slesinger PA. PLoS One. 2013;8(3):e59800. doi: 10.1371/journal.pone.0059800.

2012

Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA. Padgett CL, Lalive AL, Tan KR, Terunuma M, Munoz MB, Pangalos MN, Martínez-Hernández J, Watanabe M, Moss SJ, Luján R, Lüscher C, Slesinger PA. Neuron. 2012 Mar 8;73(5):978-89. doi: 10.1016/j.neuron.2011.12.031.

Meet the Team

Michael Fernando, BA

PhD student
Neuroscience
michael.fernando@icahn.mssm.edu

Project: Investigating neurexin alternative splicing under the context of neuropsychiatric disease.

Isabel Gameiro-Ros, PhD

Postdoctoral Fellow
Univ. Autonoma de Madrid, PhD in Pharmacology and Physiology
isabel.gameiro-ros@mssm.edu

Project: Investigating the impact of the effects of polygenic alterations related to alcohol use disorder (AUD) on the human neuronal function using iPSC-derived excitatory neurons from control individuals and AUD patients.

Ian W. Glaaser, PhD

Instructor
Columbia Univ: PhD in Pharmacology & Molecular Signaling
ian.glaaser@mssm.edu

Recipient of 2015 NIAAA NIH F32 postdoctoral fellowship

Project: Investigating the structural and molecular determinants of GIRK channel gating and modulation.

Daniel Kircher, PhD

Postdoctoral Fellow
Univ. of Texas, Austin, PhD in Pharmacology
daniel.kircher@mssm.edu

Project: Developing tools for measuring the real-time release of neuropeptides in freely behaving animals using new biosensors (i.e., CNiFERs) and custom-made Miniscopes.

Xiaofan Li, PhD

Postdoctoral Fellow
Penn State Univ, PhD in Molecular, Cellular and Integrative Biosciences
xiaofan.li@mssm.edu
Recipient of 2018 Young Investigator NARSAD

Project: Investigating molecular mechanism of how psychostimulant drugs alter the reward circuit activity.

Iya Prytkova, BS

PhD student
Neuroscience
iya.prytkova@icahn.mssm.edu
Recipient of 2019 F31 pre-doctoral NRSA

Project: Investigating the role of GIRK2 function in excitatory neurons in the context of alcohol use disorder, using hiPSC-derived neurons and a combination of electrophysiology, calcium imaging, and transcriptomic analysis.

Jaume Taura, PhD

Postdoctoral Fellow
Univ. of Barcelona, PhD in Biomedicine
Jaume.TauraIglesias@mssm.edu

Project: Investigating the neuronal activity and neurotransmitter release in the reward circuitry during alcohol intake, using fiber photometry to measure fluorescence in freely moving animals that express genetically encoded calcium and neurotransmitter indicators.

Yulin Zhao, PhD

Postdoctoral Fellow
Marquette University, PhD in Neuroscience
yulin.zhao@mssm.edu

Project: Investigating the physiological roles of the GIRK channels in the brain disorders, and developing pharmacological tools to modulate GIRK channels in these disorders.

Recognitions

2020

FBI Pilot Grant awarded to Clem and Slesinger to study Neuropeptide signaling by prefrontal interneurons in fear memory encoding

Congratulations to Iya Prytkova for being awarded a NRSA in 2019 from NIAAA for Elucidating the Role of KCNJ6 in a Human Neuronal Model of Alcohol Use Disorder

2018

Congratulations to Dr. Xiaofan Li for being awarded a 2018 Young Investigator NARSAD grant.

Dr. Paul Slesinger is the recipient of the Lillian and Henry M. Stratton Professor of Neuroscience Chair

2015

Congratulations to Robert Rifkin for his NIDA NIH F30 predoctoral fellowship and to Dr. Ian Glaaser for his NIAAA NIH F32 postdoctoral fellowship.
PMID: 29055037

Funding

Positions

We are currently seeking Postdocs. Icahn School of Medicine at Mount Sinai is seeking enthusiastic, detail-oriented applicants to join the Slesinger Lab, a multi-disciplinary team focused on the neurobiological mechanisms of drug addiction. The School is one of the nation’s leading medical schools, ranked in the top 20 schools for NIH funding. The Nash Family Department of Neuroscience at the Icahn School of Medicine is ranked number one in NIH funding and is undergoing rapid expansion. The Department offers an outstanding intellectual and multidisciplinary research environment with a commitment to translational research.

Candidates should have a Ph.D. or M.D and a strong background in molecular/cellular neuroscience. Those with experience in animal behavioral testing are particularly encouraged to apply. Interested candidates should submit their Cover Letter, Curriculum Vitae and contact information for at least three professional references.

Materials should be emailed as a single PDF file to:

Dr. Paul A. Slesinger
Lillian and Henry M. Stratton Professor of Neuroscience
Director, Center for Neurotechnology & Behavior
paul.slesinger@mssm.edu