DownloadHi-Res Photo

Susumu Tomita, PhD

Professor of Cellular and Molecular Physiology and Neuroscience

Research & Publications
Biography
News

Research Summary

My laboratory's approach to understand the brain is to reduce the brain to various components and ultimately molecules. Temporally, neurotransmission by a major excitatory neurotransmitter, glutamate, is very quick and is clearly essential for brain function; however, the modulation of brain function underlying learning, memory, emotion, cognition, etc., happens on a different time scale than that of neurotransmission. Our broad goal is to understand how basic synaptic transmission can be modulated over seconds to hours, thereby supporting complex brain functions. The efficacy of synaptic transmission is determined by glutamate concentration at the synaptic cleft and by the number and channel properties of the glutamate receptors, which can be modulated by neuronal activation (synaptic plasticity). We have uncovered a network of modulatory proteins for glutamate receptors to control their number and properties. By understanding the machinery that controls the number and channel properties of glutamate receptors, we hope to reveal the principal rules governing synaptic transmission and synaptic plasticity.

Specialized Terms: Synaptic transmission; Brain; Biochemistry; Molecular biology; Immunocytochemistry; Gene-targeted animals; Electrophysiology

Extensive Research Description

My laboratory’s approach to understand brain is to reduce brain to various components and ultimately molecules. The primary functional component of brain is the neural circuit, which are comprised of anatomical neuronal wiring and synaptic transmission. Temporally, neurotransmission by a major excitatory neurotransmitter in brain, glutamate, is very quick and is clearly essential for brain function; however, the modulation of brain function underlying learning, memory, emotion, cognition, etc., happens on a different time scale than that of neurotransmission. Our broad goal is to understand how basic synaptic transmission can be modulated over seconds to hours, thereby supporting complex brain functions.The efficacy of synaptic transmission is determined by glutamate concentration at the synaptic cleft and by the number and channel properties of the glutamate receptors, which can be modulated by neuronal activation (synaptic plasticity).

It is therefore important to determine how many receptors are at synapses and how strongly these receptors are activated upon glutamate releases. We have uncovered a network of modulatory proteins for glutamate receptors to control their number and properties. By understanding the machinery that controls the number and channel properties of glutamate receptors, we hope to reveal the principal rules governing synaptic transmission and synaptic plasticity. Combined with neuronal wiring mapping, this should help us understand a big picture of neural circuits and the momentary changes that occur in neural circuits to control animal behavior.

Coauthors

Research Interests

Biochemistry; Brain; Electrophysiology; Molecular Biology; Synaptic Transmission; Physiology

Research Image

7808127

A, TARPs consist of four isoforms (stargazin, g -3, g -4, and g -8), which show distinct expression patterns in the brain . B, TARPs (green) colocalize with the glutamatergic markers AMPA receptors (red)(left panel), but not with the GABAergic marker GAD65 (red)(right panel). C, TARPs both modulate trafficking of AMPA receptors to the synapses and control the gating and pharmacology of the channel. Oocytes injected with GluR1 alone are more sensitive to glutamate (Glu) than to kainate (KA). D, AMPA receptor subunits GluR1, GluR2 and GluR4 co-immunoprecipitate with stargazin (STG) in brain extracts from +/stg mice (+/-), but not in extracts from stg/stg mice (-/-). E, TARPs stabilize AMPA receptors at synapses through its C-terminal PDZ domain binding motif.

Selected Publications

Chemogenetic regulation of the TARP-lipid interaction mimics LTP and reversibly modifies behaviorPark J, Berthoux C, Hoyos-Ramirez E, Shan L, Morimoto-Tomita M, Wang Y, Castillo P, Tomita S. Chemogenetic regulation of the TARP-lipid interaction mimics LTP and reversibly modifies behavior. Cell Reports 2023, 42: 112826. PMID: 37471228, PMCID: PMC10528344, DOI: 10.1016/j.celrep.2023.112826.
Glutamatergic Pathways and ReceptorsTomita S. Glutamatergic Pathways and Receptors. 2023, 197-200. DOI: 10.1007/978-3-031-15070-8_30.
P-088 Radiosynthesis of 6-(2-cyclobutyl-5-(methyl-11C)-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one and (2-cyclobutyl-3-(1H-indazol-5-yl)-5-[11C]methyl-3H-imidazo[4,5-b]pyridine for imaging γ-8 dependent transmembrane AMPA receptor regulatory proteinYu Q, Kumata K, Collier T, Tomita S, Zhang M, Liang S. P-088 Radiosynthesis of 6-(2-cyclobutyl-5-(methyl-11C)-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one and (2-cyclobutyl-3-(1H-indazol-5-yl)-5-[11C]methyl-3H-imidazo[4,5-b]pyridine for imaging γ-8 dependent transmembrane AMPA receptor regulatory protein. Nuclear Medicine And Biology 2022, 108: s97-s98. DOI: 10.1016/s0969-8051(22)00225-6.
Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitationMcCarroll MN, Gendelev L, Kinser R, Taylor J, Bruni G, Myers-Turnbull D, Helsell C, Carbajal A, Rinaldi C, Kang HJ, Gong JH, Sello JK, Tomita S, Peterson RT, Keiser MJ, Kokel D. Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation. Nature Communications 2019, 10: 4078. PMID: 31501447, PMCID: PMC6733874, DOI: 10.1038/s41467-019-11936-w.
Molecular constituents and localization of the ionotropic GABA receptor complex in vivoTomita S. Molecular constituents and localization of the ionotropic GABA receptor complex in vivo. Current Opinion In Neurobiology 2019, 57: 81-86. PMID: 30784980, PMCID: PMC6629498, DOI: 10.1016/j.conb.2019.01.017.
Unexplored therapeutic opportunities in the human genome.Oprea TI, Bologa CG, Brunak S, Campbell A, Gan GN, Gaulton A, Gomez SM, Guha R, Hersey A, Holmes J, Jadhav A, Jensen LJ, Johnson GL, Karlson A, Leach AR, Ma'ayan A, Malovannaya A, Mani S, Mathias SL, McManus MT, Meehan TF, von Mering C, Muthas D, Nguyen DT, Overington JP, Papadatos G, Qin J, Reich C, Roth BL, Schürer SC, Simeonov A, Sklar LA, Southall N, Tomita S, Tudose I, Ursu O, Vidovic D, Waller A, Westergaard D, Yang JJ, Zahoránszky-Köhalmi G. Unexplored therapeutic opportunities in the human genome. Nature Reviews. Drug Discovery 2018, 17: 377. PMID: 29567993, DOI: 10.1038/nrd.2018.52.
Input-Specific NMDAR-Dependent Potentiation of Dendritic GABAergic InhibitionChiu CQ, Martenson JS, Yamazaki M, Natsume R, Sakimura K, Tomita S, Tavalin SJ, Higley MJ. Input-Specific NMDAR-Dependent Potentiation of Dendritic GABAergic Inhibition. Neuron 2018, 97: 368-377.e3. PMID: 29346754, PMCID: PMC5777295, DOI: 10.1016/j.neuron.2017.12.032.
Assembly rules for GABAA receptor complexes in the brainMartenson JS, Yamasaki T, Chaudhury NH, Albrecht D, Tomita S. Assembly rules for GABAA receptor complexes in the brain. ELife 2017, 6: e30826. PMID: 28816653, PMCID: PMC5577914, DOI: 10.7554/elife.27443.
GARLH Family Proteins Stabilize GABAA Receptors at SynapsesYamasaki T, Hoyos-Ramirez E, Martenson JS, Morimoto-Tomita M, Tomita S. GARLH Family Proteins Stabilize GABAA Receptors at Synapses. Neuron 2017, 93: 1138-1152.e6. PMID: 28279354, PMCID: PMC5347473, DOI: 10.1016/j.neuron.2017.02.023.
Glutamatergic Pathways and ReceptorsTomita S. Glutamatergic Pathways and Receptors. 2016, 231-236. DOI: 10.1007/978-3-319-24551-5_29.
CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and MemoryPark J, Chávez AE, Mineur YS, Morimoto-Tomita M, Lutzu S, Kim KS, Picciotto MR, Castillo PE, Tomita S. CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory. Neuron 2016, 92: 75-83. PMID: 27667007, PMCID: PMC5059846, DOI: 10.1016/j.neuron.2016.09.002.
Synaptic localization of neurotransmitter receptors: comparing mechanisms for AMPA and GABAA receptorsMartenson JS, Tomita S. Synaptic localization of neurotransmitter receptors: comparing mechanisms for AMPA and GABAA receptors. Current Opinion In Pharmacology 2014, 20: 102-108. PMID: 25529200, PMCID: PMC4318715, DOI: 10.1016/j.coph.2014.11.011.
Cornichons Control ER Export of AMPA Receptors to Regulate Synaptic ExcitabilityBrockie PJ, Jensen M, Mellem JE, Jensen E, Yamasaki T, Wang R, Maxfield D, Thacker C, Hoerndli F, Dunn PJ, Tomita S, Madsen DM, Maricq AV. Cornichons Control ER Export of AMPA Receptors to Regulate Synaptic Excitability. Neuron 2013, 80: 129-142. PMID: 24094107, PMCID: PMC3795439, DOI: 10.1016/j.neuron.2013.07.028.
Homeostatic Control of Synaptic Transmission by Distinct Glutamate ReceptorsYan D, Yamasaki M, Straub C, Watanabe M, Tomita S. Homeostatic Control of Synaptic Transmission by Distinct Glutamate Receptors. Neuron 2013, 78: 687-699. PMID: 23719165, PMCID: PMC3668311, DOI: 10.1016/j.neuron.2013.02.031.
PDZ binding of TARPγ-8 controls synaptic transmission but not synaptic plasticitySumioka A, Brown TE, Kato AS, Bredt DS, Kauer JA, Tomita S. PDZ binding of TARPγ-8 controls synaptic transmission but not synaptic plasticity. Nature Neuroscience 2011, 14: 1410-1412. PMID: 22002768, PMCID: PMC3206644, DOI: 10.1038/nn.2952.
Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1Straub C, Hunt DL, Yamasaki M, Kim KS, Watanabe M, Castillo PE, Tomita S. Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1. Nature Neuroscience 2011, 14: 866-873. PMID: 21623363, PMCID: PMC3125417, DOI: 10.1038/nn.2837.
Hippocampal AMPA Receptor Gating Controlled by Both TARP and Cornichon ProteinsKato AS, Gill MB, Ho MT, Yu H, Tu Y, Siuda ER, Wang H, Qian YW, Nisenbaum ES, Tomita S, Bredt DS. Hippocampal AMPA Receptor Gating Controlled by Both TARP and Cornichon Proteins. Neuron 2010, 68: 1082-1096. PMID: 21172611, PMCID: PMC3034222, DOI: 10.1016/j.neuron.2010.11.026.
TARP Phosphorylation Regulates Synaptic AMPA Receptors through Lipid BilayersSumioka A, Yan D, Tomita S. TARP Phosphorylation Regulates Synaptic AMPA Receptors through Lipid Bilayers. Neuron 2010, 66: 755-767. PMID: 20547132, PMCID: PMC2887694, DOI: 10.1016/j.neuron.2010.04.035.
A Transmembrane Accessory Subunit that Modulates Kainate-Type Glutamate ReceptorsZhang W, St-Gelais F, Grabner CP, Trinidad JC, Sumioka A, Morimoto-Tomita M, Kim KS, Straub C, Burlingame AL, Howe JR, Tomita S. A Transmembrane Accessory Subunit that Modulates Kainate-Type Glutamate Receptors. Neuron 2009, 61: 385-396. PMID: 19217376, PMCID: PMC2803770, DOI: 10.1016/j.neuron.2008.12.014.
PDZ Protein Interactions Regulating Glutamate Receptor Function and PlasticityTomita S, Nicoll R, Bredt D. PDZ Protein Interactions Regulating Glutamate Receptor Function and Plasticity. Journal Of Cell Biology 2001, 153: f19-f24. PMID: 11381098, PMCID: PMC2174328, DOI: 10.1083/jcb.153.5.f19.
Overexpression of Human Amyloid Precursor Protein in DrosophilaYagi Y, Tomita S, Nakamura M, Suzuki T. Overexpression of Human Amyloid Precursor Protein in Drosophila. Archives Of Biochemistry And Biophysics 2000, 4: 43-49. PMID: 11152627, DOI: 10.1006/mcbr.2000.0248.
Regulation of X11L-dependent Amyloid Precursor Protein Metabolism by XB51, a Novel X11L-binding Protein*Lee D, Tomita S, Kirino Y, Suzuki T. Regulation of X11L-dependent Amyloid Precursor Protein Metabolism by XB51, a Novel X11L-binding Protein*. Journal Of Biological Chemistry 2000, 275: 23134-23138. PMID: 10833507, DOI: 10.1074/jbc.c000302200.
Isolation and characterization of a cDNA encoding a novel drosophila APPL binding proteinTaru H, Yagi Y, Hase M, Tomita S, Kirino Y, Suzuki T. Isolation and characterization of a cDNA encoding a novel drosophila APPL binding protein. Neurobiology Of Aging 2000, 21: 256. DOI: 10.1016/s0197-4580(00)83102-4.
PDZ Domain-dependent Suppression of NF-κB/p65-induced Aβ42 Production by a Neuron-specific X11-like Protein*Tomita S, Fujita T, Kirino Y, Suzuki T. PDZ Domain-dependent Suppression of NF-κB/p65-induced Aβ42 Production by a Neuron-specific X11-like Protein*. Journal Of Biological Chemistry 2000, 275: 13056-13060. PMID: 10777610, DOI: 10.1074/jbc.c000019200.
Interaction of a Neuron-specific Protein Containing PDZ Domains with Alzheimer's Amyloid Precursor Protein*Tomita S, Ozaki T, Taru H, Oguchi S, Takeda S, Yagi Y, Sakiyama S, Kirino Y, Suzuki T. Interaction of a Neuron-specific Protein Containing PDZ Domains with Alzheimer's Amyloid Precursor Protein*. Journal Of Biological Chemistry 1999, 274: 2243-2254. PMID: 9890987, DOI: 10.1074/jbc.274.4.2243.
A Basic Amino Acid in the Cytoplasmic Domain of Alzheimer's β-Amyloid Precursor Protein (APP) Is Essential for Cleavage of APP at the α-Site*Tomita S, Kirino Y, Suzuki T. A Basic Amino Acid in the Cytoplasmic Domain of Alzheimer's β-Amyloid Precursor Protein (APP) Is Essential for Cleavage of APP at the α-Site*. Journal Of Biological Chemistry 1998, 273: 19304-19310. PMID: 9668120, DOI: 10.1074/jbc.273.30.19304.
Cleavage of Alzheimer's Amyloid Precursor Protein (APP) by Secretases Occurs after O-Glycosylation of APP in the Protein Secretory Pathway IDENTIFICATION OF INTRACELLULAR COMPARTMENTS IN WHICH APP CLEAVAGE OCCURS WITHOUT USING TOXIC AGENTS THAT INTERFERE WITH PROTEIN METABOLISM*Tomita S, Kirino Y, Suzuki T. Cleavage of Alzheimer's Amyloid Precursor Protein (APP) by Secretases Occurs after O-Glycosylation of APP in the Protein Secretory Pathway IDENTIFICATION OF INTRACELLULAR COMPARTMENTS IN WHICH APP CLEAVAGE OCCURS WITHOUT USING TOXIC AGENTS THAT INTERFERE WITH PROTEIN METABOLISM*. Journal Of Biological Chemistry 1998, 273: 6277-6284. PMID: 9497354, DOI: 10.1074/jbc.273.11.6277.
cDNA isolation of Alzheimer's amyloid precursor protein from cholinergic nerve terminals of the electric organ of the electric rayIIJIMA K, LEE D, OKUTSU J, TOMITA S, HIRASHIMA N, KIRINO Y, SUZUKI T. cDNA isolation of Alzheimer's amyloid precursor protein from cholinergic nerve terminals of the electric organ of the electric ray. Biochemical Journal 1998, 330: 29-33. PMID: 9461486, PMCID: PMC1219103, DOI: 10.1042/bj3300029.

Edit Profile

Susumu Tomita, PhD

Contact Information

Related Links

Research & Publications

Biography

News