TRP channel function in thermosensation, pain, and inflammation  Michael Caterina
Solomon H. Snyder Professor of Neurosurgery
of Biological Chemistry
Johns Hopkins University School of Medicine
725 N. Wolfe St. 408 Biophysics Building
Baltimore, MD 21205 Email: caterina@jhmi.edu
Office Phone: 410-955-5759
Lab Phone: 410-614-1230  Download CV (requires Adobe Reader)
Visit my Lab Page Program DescriptionMy lab studies mechanisms underlying pain sensation. One focus of the lab is a group of ion channel proteins of the Transient Receptor Potential Vanilloid (TRPV) family. These channels share the intriguing feature that they can be activated by warm or painfully hot temperatures, as well as by many nonthermal stimuli. For example, TRPV1, the founding member of this family, can be activated by painful heat (>42°C), by protons, or by pungent chemicals such as capsaicin. This channel is strongly expressed in nociceptive neurons and is essential for normal behavioral responses to noxious heat. By examining these channels in recombinant and native systems, and taking advantage of knockout mice lacking one or more subtypes, we are dissecting the biological contributions of these channels to pain sensation and other processes in both neuronal and nonneuronal cells. A second focus of the lab is the use of cutting-edge molecular, cellular, genetic, behavioral and physiological approaches to understand the biological and pathophysiological basis of chronic pain in animal models and in human disease.
Current areas of emphasis include:
- Understanding the mechanisms by which keratinocytes in the skin contribute to "indirect" pain perception by signaling to epidermal nerve endings under healthy conditions and in painful disease states in both animal models and human patients.
- Uncovering non-nociceptive roles for TRPV channels in epithelial cells of the skin and urinary bladder.
- Developing novel assays and reagents for the quantification and characterization of acute nociception and chronic pain.
- Dissecting the cellular and molecular events that contribute to neuropathic pain and exploring strategies to reverse this condition.
Recent PublicationsMunns CH, Chung MK, Amzel LM, and Caterina MJ. (2015) Role of the outer pore domain in TRPV1 dynamic permeability to large cations. J. Biol Chem. 290: 5707-5724. PMID: 25568328
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Pang Z, Sakamoto T, Kim YS, Yang F, Guan Y, Dong X, Guler A, Caterina MJ. Keratinocyte stimulation is sufficient to evoke nociception in the mouse (2015) Pain Apr;156(4):656-65. (cover article) PMID: 25790456
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Hua ZL, Jeon S, Caterina MJ, and Nathans JN. Frizzled3 is required for the development of multiple axon tracts in the mouse central nervous system. Proc. Natl. Acad. Sci. U.S.A. Jul 22;111(29):E3005-14.PMID: 24799694
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Kim YS, Chu Y, Han L, Li M, Li Z, LaVinka PC, Sun S, Tang Z, Park K, Caterina MJ, Ren K, Dubner R, Wei F and Dong X. Central Terminal Sensitization of TRPV1 by Descending Serotonergic Facilitation Modulates Chronic Pain. Neuron (2014) Feb 19;81(4):873-87. PMID: 24462040
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Caterina MJ (2014) TRP channel cannabinoid targets and skin inflammation ACS Chem Neurosci. 5(11):1107-16 PMID: 24915599
Park U, Vastani N, Guan Y, Raja S, Koltzenberg M. and Caterina MJ. TRPV2 knockout mice are susceptible to perinatal lethality but display normal thermal and mechanical nociception (2011) J Neurosci. 31(32):11425-36.
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Huang SM, Li X, Yu Y, Wang J, Caterina MJ. TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation. (2011) Mol Pain. 2011 May 17;7(1):37.
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Cheng X, Jin, J, Hu L, Shen D, Dong X, Samie MA, Knoff J, Eisinger B, Liu M, Huang SM, Caterina MJ, Dempsey P, Michael E, Dlugosz A, Andrews NC, Clapham DE, and Xu H. A Keratinocyte TRP Channel Controls Hair Morphogenesis and Skin Barrier Formation via EGFR signaling and Transglutaminase Activity. (2010) Cell 141, 331-343.
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Link TM, Park U, Vonakis BM, Raben DM, Soloski MJ, Caterina MJ. TRPV2 has a pivotal role in macrophage particle binding and phagocytosis. (2010) Nature Immunology 11, 232-239.
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Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H, Shi Y, Taye AA, Kong L, Munns CH, Choo SS, Phelps CB, Paudel R, Houlden H, Ludlow CL, Caterina MJ, Gaudet R, Kleta R, Fischbeck KH, Sumner CJ. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C Nature Genet. (2010) Feb;42(2):170-4.
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Huang SM, Lee H, Chung MK, Park, U, Yu YY, Bradshaw H, Coulombe PA, Walker JM, and Caterina MJ. Skin keratinocyte TRPV3 ion channels modulate pain sensitivity via prostaglandin E2. (2008) J. Neurosci. 28, 13727-13737.
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Chung MK, Guler AD and Caterina MJ. TRPV1 exhibits dynamic ionic selectivity during agonist stimulation. (2008) Nature Neuroscience 11, 555-564 (Highlighted in Nat Neurosci. 2008 May;11(5):528-9)
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Moussaieff A, Rimmerman N, Bregman T, Straiker A, Felder CC, Shoham S, Kashman Y, Huang SM, Lee H, Shohami E, Mackie K, Caterina MJ, Walker JM, Fride E and Mechoulam R. Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain (2008) FASEB J 22(8):3024-34.
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Lumpkin EA and Caterina MJ. Mechanisms of Sensory Transduction in the Skin. (2007) Nature 445(7130):858-65.
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Birder L, Negoita F, Lee H, de Groat W, Kanai A, Barrick S, Meyers S, and Caterina, MJ. Activation of Urothelial-TRPV4 by 4a-PDD contributes to altered bladder reflexes in the rat. (2007) J Pharmacol Exp Ther. 323(1):227-35. PubMed Reference
Sidhaye VK, Guler AD, Schweitzer KS, D’Alessio F, Caterina MJ and King LS Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions. (2006) Proc. Natl. Acad. Sci., USA 103(12):4747-52.
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Shimizu I, Iida T, Horiuchi N and Caterina MJ. 5-Iodoresiniferatoxin evokes hypothermia in mice and is a partial TRPV1 agonist in vitro .(2005) J. Pharm. Exp. Ther., 314:1378-85.
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Shimizu I, Iida T, Guan Y, Zhao C, Raja SN, Jarvis MF, Cockayne DA, and Caterina MJ. Enhanced thermal avoidance in mice lacking the ATP receptor P2X3. (2005) Pain, 116, 96-108.
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Pogatzki-Zahn E,, Shimizu I, Caterina MJ and Raja SN. Heat hyperalgesia after incision requires TRPV1 and is distinct from pure inflammatory pain. (2005) Pain, 115, 296-307.
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Chung MK, Guler AD, and Caterina MJ. Biphasic currents evoked by chemical or thermal activation of the heat-gated ion channel, TRPV3. (2005) J. Biol Chem. 280, 15928-15941.
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Lee H, Iida T, Mizuno A, Suzuki M, Caterina MJ. Altered thermal preference in mice lacking TRPV4. (2005) J. Neurosci. 25 1304-10.
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Iida T, Shimizu I, Nealen ML, Campbell, A., and Caterina MJ. Attenuated fever response in mice lacking TRPV1. (2005) Neurosci. Lett. 378, 28-33.
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Chung MK, Lee H, Mizuno A, Suzuki M, Caterina MJ. 2-aminonethoxydiphenyl borate activates and sensitizes the heat-gated ion channel, TRPV3. (2004) J. Neurosci. 24, 5177-5182.
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Chung MK, Lee H, Mizuno A, Suzuki M, Caterina MJ . TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. (2004) J Biol. Chem. 279, 21569-21575. PubMed Reference
Nealen M, Thut P, Gold M and Caterina MJ. TRPM8 is expressed in a subset of cold-responsive trigeminal neurons from rat. (2003) J. Neurophysiology 90, 515-520. PubMed Reference
Birder LA, Nakamura Y, Kiss S, Nealen ML, Barrick S, Kanai AJ, Wang E, Ruiz G, De Groat WC, Apodaca G, Watkins S, Caterina M.J. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. (2002) Nature Neurosci. 5, 856-860. PubMed Reference
Guler A, Lee H, Iida T, Shimizu I, Tominaga M, and Caterina MJ. Heat-evoked activation of the ion channel, TRPV4. (2002) J. Neurosci. 22, 6408-6414. PubMed Reference
Caterina MJ, Leffler A, Malmberg A, Martin W, Trafton J, Petersen-Zeitz KR, Koltzenberg M, Basbaum A and Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306-313. (cover article) PubMed Reference
Caterina MJ, Rosen A, Tominaga M, Brake AJ, and Julius D (1999) A capsaicin receptor homologue with a threshold for noxius heat. Nature, 398, 436-441. PubMed Reference
Caterina MJ, Schumacher M, Tominaga M,, Rosen TA, Levine JD and Julius, D. The capsaicin receptor, a heat-activated ion channel in the pain pathway. (1997) Nature, 389, 816-824. PubMed Reference Molecular Mechanisms of Synapse Formation in Development and Disease Program DescriptionSynapses are specialized cell-cell junctions which connect individual neurons together and are the sites of transmission of information between neurons. While the molecular mechanisms which promote synapse formation have been a subject of intense investigation, little is known about the molecular mechanisms that limit synapse formation so that synapses form at the right time and place and in the correct numbers. We hypothesize that this step in the refinement of synaptic formation is crucial for the fine-tuning of neuronal connectivity and that signaling networks which limit synapses during development are either defective or inappropriately activated in cognitive disorders. Accordingly, our laboratory studies the signaling pathways that regulate synapse formation during normal brain development to begin to understand how, when these pathways go awry, human cognitive disorders develop.
Currently projects include studies of:
1) Ephexin5: Ephexin5 is a guanine nucleotide-exchange factor (GEF) that activates the small G-protein RhoA, a regulator of the actin cytoskeleton. Genetic loss- and gain-of-function studies indicate that Ephexin5 acts to restrict spine growth and synapse development in the developing brain. Upon induction of EphrinB/EphB ligand-receptor signaling, Ephexin5 is rapidly phosphorylated in an EphB-dependent manner and targeted for proteasome-dependent degradation. These findings suggest that Ephexin5 functions as a barrier to excitatory synapse development until its degradation is triggered by EphrinB binding to EphBs. Interestingly, the degradation of Ephexin5 is mediated by Ube3A, a ubiquitin ligase whose expression level is altered in the human cognitive disorder Angelman Syndrome (AS) and in some forms of autism. This suggests that aberrant EphB/Ephexin5 signaling during synaptic development may contribute to the abnormal cognitive function observed in AS and autism.
Using Ephexin5 our laboratory will pursue an understanding of the molecular pathways that regulate restriction of excitatory synapse formation and their relevance to the pathophysiology of Angelman Syndrome by addressing the following questions: 1) What are the molecular determinants critical for Ube3A-mediated control of Ephexin5 degradation? 2) What molecular and cellular events underlie Ephexin5-mediated excitatory synapse restriction important for basic wiring of the nervous system? 3) What additional substrates of Ube3A are important for synapse formation?
2) New regulators of synapse formation: The goal of this study will be to identify additional components of the genetic program that restrict synapse numbers using previously developed immunocytochemistry-based assay for neuronal synaptic connections in vitro. Specific targets will be corroborated using electrophysiological and in vivo morphological measurements. We are particularly interested in genes whose products function to restrict synapse formation early in development and are suggested to be defective or inappropriately activated in cognitive disorders. Recent PublicationsMargolis SS*, Salogiannis J*, Lipton DM, Mandel-Brehm C, Wills ZP, Mardinly AR, Hu L, Greer PL, Bikoff JB, Ho H-YH, Soskis, MJ , Sahin M, Greenberg ME . EphB mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell. 2010 Nov 29; 143 (4): 442-55.
PubMed Reference Comment in “Cell”: Dalva MB. (2010) Ephecting excitatory synapse development. Cell. 29;143(3):341-2.
PubMed Reference The Regulation of Neuronal Gene Expression in Health and Disease  Mollie K. Meffert
Associate Professor
of Biological Chemistry
Johns Hopkins University School of Medicine
725 N. Wolfe St
Baltimore, MD 21205 Email: mkm@jhmi.edu
Office Phone: 410-955-5759
Lab Phone: 410-502-2571 Visit my Lab Page Program DescriptionOur laboratory is particularly interested in how changes in synaptic activity are converted into long-term alterations in the function and connectivity of neurons through the modulation of gene expression. Fundamental questions in gene expression of interest to the lab include: Why are changes in gene expression required for enduring alterations in synaptic strength, such as during learning, development, or disease? What pathways exist to generate distinct subcellular changes in gene expression, for example to regulate individual synapse protein composition and input specificity? How do diverse neuronal stimuli induce specific patterns of gene expression on a synapse, cellular, or network level? What mechanisms maintain changes in gene expression? Our laboratory integrates multiple approaches to address the importance of gene expression in information storage at both transcriptional and post-transcriptional levels. We use animal models and techniques of molecular biology, cell biology, biochemistry, high-throughput expression analysis and bioinformatics, virology, histology, confocal imaging, electrophysiology, mouse genetics and behavior. Neuronal gene products of interest include both proteins and non-coding RNAs. Study of the NF-κB transcription factor provides a good vantage point from which to explore transcriptional regulation in neurons. NF-κB has emerged as a key player in many CNS diseases, including neurodegenerative disorders and cancer. In the healthy CNS, studies from multiple laboratories including our own have demonstrated an evolutionarily conserved requirement for NF-κB in learning and memory. NF-κB is present at synapses and can undergo activation and nuclear translocation from distal processes upon synaptic stimulation. A current focus of our lab is to understand the signaling by the synaptic pool of NF-κB and how NF-κB regulates neuronal functions in both plasticity and disease. Gene expression in the nervous system can be rapidly altered by control at the level of translation. Changes in translation, like transcription, are also critical for long-term information storage. A second major focus of our laboratory investigates how target specificity is generated in response to neuronal stimuli that regulate protein synthesis. We have discovered that the translating pool of RNA may be controlled through both positive and negative regulation of the biogenesis of mature microRNA from precursor microRNA. Ongoing investigations in our laboratory are aimed at further exploration of the importance of micoRNA biogenesis in determining rapid and specific changes in the neuronal and synaptic proteome and the in vivo roles of these pathways in healthy and dysregulated brain function. For images of our work
Recent links to our work:
Neuroscience Innovations
Videos showing increased mRNA repression (RNA-processing bodies) in live neurons responding to BDNF:
Messenger RNA accumulates in a neuron
BDNF-treated neuron Recent PublicationsHuang*Y-WA, Ruiz*CR, Eyler ECH*, Lin K, and Meffert MK (2012). Dual regulation of miRNA biogenesis generates target specificity in neurotrophin-induced protein synthesis. Cell, 148(5); 933-946.
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Boersma* MC, Dresselhaus*EC, De Biase LM, Mihalas AB, Bergles DE, and Meffert MK (2011), A requirement for NF-kB in developmental and plasticity-associated synaptogenesis. J.Neurosci., 31; 5414-5425.
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Shrum CK, Defrancisco D, and Meffert MK. (2009) Stimulated nuclear translocation of NF-kB and shuttling differentially depend on dynein and the dynactin complex. PNAS, 106; 2647-2652.
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Boersma MC and Meffert MK (2008) Novel roles for the NF-kB signaling pathway in regulating neuronal function. Science Signaling 1, pe7.
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Shrum CK and Meffert MK (2008). The NF- kB Family in Learning and Memory. In J. David Sweatt(Ed.), Molecular Mechanisms of Memory. Vol. [4] of Learning and Memory: A Comprehensive Reference (J.Byrne Editor), pp. [567-586] Oxford: Elsevier
Science Direct
Mattson MP and Meffert MK (2006). Roles for NF-kB in nerve cell survival, plasticity, and disease. Cell Death and Differentiation 13, 852-60.
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Meffert MK and Baltimore D (2005). Physiological functions for brain NF-kB. Trends in Neurosciences 28, 37-43.
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Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D (2003). NF-kB functions in synaptic signaling and behavior. Nature Neuroscience 6, 1072 - 1078.
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Meffert MK, Calakos NC, Scheller RH, Schulman H (1996). Nitric oxide modulates synaptic vesicle docking / fusion reactions. Neuron 16, 1229-1236.
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Meffert*MK, Haley*JE, Schuman EM, Schulman H, and Madison DV (1994). Inhibition of hippocampal heme oxygenase, nitric oxide synthase and long-term potentiation by metalloporphyrins. Neuron 13, 1225-1233.
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Meffert MK, Premack BA, and Schulman H (1994). Nitric oxide stimulates calcium-independent synaptic vesicle release. Neuron 12, 1235-1244.
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Schuman EM, Meffert MK, Schulman H, Madison DV (1994). An ADP-Ribosyltransferase as a Target for Nitric Oxide Action in Long-Term Potentiation. Proceedings of the National Academy of Sciences 91, 11958-11962.
PubMed Reference Structure, function, regulation and interfacial enzymology of lipid metabolizing enzymes involved in signal transduction cascades; biochemistry and chemistry of lipids and lipid metabolizing enzymes involved in signaling cascades. Program DescriptionA major effort in our laboratory is focused on understanding the biochemistry and chemistry underlying the molecular aspects involved in regulating lipid metabolizing signaling enzymes and the physiological roles of this regulation. Control of lipid metabolizing enzymes involves the modulation of two key parameters; their sub-cellular distribution and their intrinsic enzymatic activity. Our studies have concentrated on three families of lipid-metabolizing signaling enzymes: diacylglycerol kinases, phospholipases D, and phospholipases C.
Specific Areas of Interest
Interfacial Enzymology of Lipid Metabolizing Signaling Enzymes: We are particularly interested in identifying the critical modulating proteins, lipids, and post-translational modifications that alter the localization and/or activity of lipid metabolizing enzymes. In these studies we consider the fact that these enzymes act as interfacial enzymes and their regulation includes a number of interfacial-dependent parameters. Our recent studies have identified some of the diacylglycerol metabolizing enzyme DGK-θ (diacylglycerol kinase-theta) interfacial parameters that are altered upon neuronal depolarization. Further, our studies demonstrated that activation of DGK-θ requires a protein that contains a polybasic region. We have recently obtained evidence that identifies at least one, if not only, activator binding domain on DGK-θ.
Enzyme Structure/Function Studies: We are also interested in the structural components of these enzymes that are critical for their distribution/re-distribution to specific sub-cellular compartments. Additionally, and to compliment the enzymology studies, we are interested in elucidating the catalytic mechanism(s) of these enzymes. These studies will be conducted partly in collaboration with Dr. Mario Amzel. Our long-term goal is to understand the biochemistry and chemistry of these enzymes and determine how changes in their sub-cellular localization and/or enzymatic activity affect their signaling functions.
Physiological Functions of DGKs in Neurons: There is growing evidence that DGKs play physiological roles in mammalian neurons. This evidence includes cellular localization of specific isoforms, and the observations that likely modulate (a) susceptibility to epileptic seizures (DGK-), (b) neuronal spine density (DGK- and DGK-), and (c) pre-synaptic glutamate release during DHPG (3,5-dihydroxyphenylglycine)-induced long-term potentiation (DGK-). We are currently examining the role of DGK-θ in glutamatergic neurons. These studies have initially focused on identifying the physiologic regulator of DGK-θ, and test the hypothesis that this enzyme modulates induced glutamate release in these mammalian neurons. We discovered that DGK-θ modulates glutamate release from cortical and hippocampal neurons in part by modulating synaptic vesicle cycling. These studies are conducted in collaboration with Dr. Rick Huganier’s laboratory. Recent PublicationsTu-Sekine, B., Goldschmidt, H, Raben, D.M. (2015) Diacylglycerol, Phosphatidic Acid, and their Metabolizing Enzymes in Synaptic Vesicle Recycling. Adv. Biol. Reg. Jan;57:147-52.
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Petro E, and Raben DM. (2013) Bacterial expression strategies for several Sus scrofa diacylglycerol kinase alpha constructs: solubility challenges. Scientific Reports 2013;3:160.
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Ueda S, Tu-Sekine B, Yamanoue M, Raben DM, and Shirai Y. (2013) The expression of diacylglycerol kinase theta during the organogenesis of mouse embryos. BMC Developmental Biology 2013, 13:35.
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Bolduc D, Rahdar M, Tu-Sekine B, Sivakumaren SC, Raben DM, Amzel LM, Devreotes P, Gabelli SB, and Cole P. (2013) Phosphorylation-mediated PTEN conformational closure and deactivation revealed with protein semisynthesis. Elife 2013 Jul 9;2:e00691.
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Tu-Sekine B, Goldschmidt H, Petro E, and Raben DM. (2013) Diacylglycerol Kinase Theta: Regulation and Stability. Adv. Biol. Reg. Jan;53(1):118-26.
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Tu-Sekine B, and Raben DM. (2012) Dual Regulation of DGK-θ: Polybasic Proteins Promote Activation by Phospholipids and Increase Substrate Affinity. J. Biol. Chem. 287(50):41619-41627.
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Tu-Sekin, B, and Raben DM. (2011) Regulation and Roles of Neuronal Diacylglycerol Kinases: a Lipid Perspective. Crit. Rev. Biochem. Mol. Biol. Oct;46(5):353-64.
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Mohan S, Tse CM, Gabelli SB, Sarker R, Cha B, Fahie K, Nadella M, Zachos NC, Tu-Sekine B, Raben DM, Amzel LM, Donowitz M. (2010) NHE3 Activity Is Dependent on Direct Phosphoinositide Binding at the N Terminus of Its Intracellular Cytosolic Region. J. Biol. Chem. 285(45): 34566-78.
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Tu-Sekine, B. and Raben DM. (2010) Characterization of Cellular DGKΘ. Advances in Enzyme Reg. 50:81-94.
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Link TM, Park U, Vonakis BM, Raben DM, Soloski M.J., Caterina MJ. (2010) TRPV2 plays a pivotal role in macrophage particle binding and phagocytosis. Nature Immunology Mar;11(3):232-9. Epub 2010 Jan 31.
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Tu-Sekine and Raben DM. (2009) Regulation of DGK-Θ J. Cell Physiol. 220(3):548-52.
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Raben DM and Wattenberg BW. (2009) Signaling at the Membrane Interface by the DGK/SK Enzyme Family. J Lipid Res 50th Anniversary Edition: J. Lipid Res. April Supplement: S35-S39.
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Raben DM and Tu-Sekine B. (2008) Nuclear Localization Of Diacylglycerol Kinases: Regulation And Roles. Frontiers in Bioscience 13:590-597.
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Wattenberg BW and Raben DM. (2007) Diacylglycerol Kinases Put the Brakes on Immune Function. Science STKE (398) pe43.
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Tu-Sekine B, Ostroski M, and Raben DM. (2007) Modulation of DGKΘ Activity by α-Thrombin and Phospholipids. Biochemistry, 46(3): 924 -932.
PubMed Reference Cellular and organismal metabolism Program DescriptionOur laboratory is interested in understanding the metabolic properties of neurons and glia at a mechanistic level in situ. Some of the most interesting, enigmatic and understudied cells in metabolic biochemistry are those of the nervous system. Defects in these pathways can lead to devastating neurological disease. Conversely, altering the metabolic properties of the nervous system can have surprisingly beneficial effects on the progression of some diseases. However, the mechanisms of these interactions are largely unknown.
We utilize biochemical and molecular genetic techniques to understand the molecular mechanisms that the nervous system uses to sense and respond to metabolic cues. We have uncovered novel neuronal nutrient sensing paradigms that act through unique metabolic enzymes to control body weight and diabetes susceptibility. We continue to explore novel neuron-specific enzyme function in metabolic processes as well as uncovering novel roles of canonical metabolic pathways in the nervous system. Furthermore, the unique makeup of the nervous system requires our laboratory to develop new technology and assays to facilitate our work.
Below are the broad areas that we are currently focusing on.
- Deconstructing neurometabolic pathways. How does the nervous system utilize bioenergetic substrates and how does the disruption of these pathways affect animal behavior and physiology? Here we use tissue specific gain and loss of function mouse models to understand the biochemistry of the nervous system and how these metabolic pathways impact animal behavior and physiology. We are currently investigating several neuron-specific and canonical enzymes in fatty acid biochemistry.
- Metabolic heterogeneity. The nervous system represents a unique challenge for biochemists in part because of the great diversity of neurons and glia, and the abundant metabolite shuttling that occurs between cells. To understand metabolism in the nervous system, we must understand how these different cells contribute uniquely to metabolic processes. Here we are developing novel tools to measure and manipulate metabolic pathways in single cells in vivo.
- The evolution of metabolic adaptation. Nature has performed some of the most elegant experiments over an enormous time scale. Understanding how enzymes have changed over time or in species that are under different environmental stress can be invaluable to understanding ourselves. Here we try to ask many of the why questions in metabolism. Why has carbohydrate metabolism been selected for the brain over and over again in almost every species? What is the consequence of changing bioenergetics substrates?
Recent PublicationsEllis JM, Wong GW & Wolfgang MJ. Acyl Coenzyme A Thioesterase 7 regulates neuronal fatty acid metabolism to prevent neurotoxicity. Mol Cell Biol. 2013; 33(9) 1869-1882.
PubMed Reference Ellis JM & Wolfgang MJ. A genetically encoded metabolite sensor for malonyl-CoA. Chemistry & Biology 2012 Oct 26; 19(10) 1333-1339. PubMed Reference
Miyamoto T, DeRose R, Suarez A, Ueno T, Chen M, Sun T, Wolfgang MJ, Mukherjee C, Meyers DJ and Inoue T. Generation of Intracellular Logic Gates with Two Orthogonal Chemically Inducible Systems. Nature Chemical Biology 2012, Mar 25;8(5):465-70.
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Rodriguez S & Wolfgang MJ. Targeted chemical-genetic regulation of protein stability in vivo. Chemistry & Biology 2012, Mar 23;19(3):391-8.
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Reamy AA & Wolfgang MJ. Carnitine Palmitoyltransferase-1C gain-of-function in the brain results in postnatal microencephaly. Journal of Neurochemistry. 2011 Aug; 118(3) 388-98.
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Cha SH, Wolfgang M, Tokutake Y, Chohnan S, Lane MD. Differential effects of central fructose and glucose on hypothalamic malonyl-CoA and food intake. Proc Natl Acad Sci USA. 2008;105(44):16871-5.
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Wolfgang MJ, Cha SH, Millington DS, Cline G, Shulman GI, Suwa A, Asaumi M, Kurama T, Shimokawa, T & Lane MD. Brain-specific carnitine palmitoyltransferase-1c: Role in CNS fatty acid metabolism, food intake and body weight. J Neurochem 2008; May;105(4):1550-9.
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Wolfgang MJ, Cha SH, Sidhaye A, Chohnan S, Cline G, Shulman GI & Lane MD. Regulation of hypothalamic malonyl-CoA by central glucose and leptin. Proc Natl Acad Sci USA. 2007 Dec; 104(49): 19285-19290.
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Chakravarthy MV, Zhu Y, López M, Yin L, Wozniak DF, Coleman T, Hu Z, Wolfgang M, Vidal-Puig A, Lane MD & Semenkovich CF. Brain fatty acid synthase activates PPARa to maintain energy homeostasis. J Clin Invest. 2007; 117: 2539-2552.
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Wolfgang MJ & Lane MD. The role of hypothalamic malonyl-CoA in energy homeostasis. J. Biol. Chem. 2006; 281(49): 37265-37269.
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Wolfgang MJ, Kurama T, Dai Y, Suwa A, Asaumi M, Matsumoto S, Cha SH, Shimokawa T & Lane MD. The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. Proc. Natl. Acad. Sci. USA 2006 May; 103(19): 7282-7287.
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Gao Q*, Wolfgang MJ*, Neschen S, Morino K, Horvath, TL, Shulman GI, & Fu XY. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility and thermal dysregulation. Proc. Natl. Acad. Sci. USA 2004 March; 101(13): 4661-4666. (*equal contribution).
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Kano A*, Wolfgang MJ*, Gao Q*, Jacoby J, Chai GX, Hansen W, Iwamoto Y, Pober JS, Flavell RA, & Fu XY. Endothelial cells require STAT3 for protection against endotoxin-induced inflammation. J Exp Med. 2003; 198(10): 1517-1525. (*equal contribution).
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