Kwang Mook Jung
Assistant Adjunct Professor, Pharmacology
|endocannabinoids, lipid molecules, pathogenesis, neurological diseases|
|URLs||Pharmacology Home Page|
|See below for selected publications or click here for additional publication listings available via PubMed|
|Appointments||2000-2004, Columbia University, Postdoc, Molecular and Cell Biology|
Statement of Research
Recent evidences on the endocannabinoids (eCB) indicate that the novel class of endogenous lipid molecules has fundamental roles in the regulation of various biological activities. I am interested in defining the molecular mechanism underlying the physiological regulation of eCB and, in particular, their relevance to the pathogenesis of certain neurological diseases.
The “endo-cannabinoids” are named after the main psychoactive ingredient in the cannabis plant, ?9-tetrahydrocannabinol (THC), which hijacks the eCB system through its binding to type-1 cannabinoid (CB1) receptors, to exert its effects. In contrast to compounds such as THC, eCB molecules – anandamide and 2-arachidonoylglycerol (2-AG) – are produced in the body upon demand and activate CB1 receptors. Previous work in our lab and others suggests that the brain eCBs serve important functions in the modulation of various long- and short-term changes in synaptic efficiency related to emotion, pain, appetite and memory. eCB signaling is also associated with several pathological conditions such as inflammation, drug addiction and neurodegenerative disorders, indicating a therapeutic potential of targeting this system. However, the mechanisms which cause these pathologies are mostly unknown. Therefore, elucidating the detailed mechanism underlying the regulation of eCBs in both normal as well as diseased conditions are important subjects for future studies.
The role of eCB in the pathogenesis of Alzheimer’s disease
Recent findings on the molecular pathology of Alzheimer’s disease (AD) converge on the idea that toxic species of soluble oligomeric forms of A? are responsible for the early cognitive impairment of AD, through the interference of synaptic modulation and spine morphology. However, the molecular mechanism by which this synaptic dysfunction is caused has not been elucidated.
Using a mass-spectrometry-based lipid quantification of post mortem brain of AD patients, I have examined whether changes in eCB signaling contribute to cognitive dysfunction in AD. I found that frontal and temporal cortex of AD patients contain significant less anandamide as well as its precursor NArPE, compared to controls. The decreased anandamide production was associated with the increase of brain A?42 and of area-specific cognitive impairments determined by clinical neuro-psychology tests. In a cellular model, increase in A? accumulation caused decreases in both anandamide and NArPE levels. These studies suggest that A?42-dependent suppression of anandamide production in the brain contributes to cognitive dysfunction in AD.
These studies open the door to further research in defining the mechanism by which deficits in eCB signaling contribute to A?-induced synaptic pathogenesis in AD. I will use a combination of biochemical and molecular biological approaches to (i) further identify the molecular mechanisms underlying the eCB deficits; and (ii) to determine whether alterations in the eCB system mediate A?-derived pathogenic changes in AD. To answer the latter question, I will specifically ask (a) what is the molecular mechanism of A?-triggered eCB deficits in a cellular model of AD; and (b) whether A?-induced synaptic abnormality, such as spine loss, is associated with the disruption of eCB signaling.
This research receives a three-year support from the Alzheimer’s Association Investigator-Initiated Research Grant, and after successful completion of the funded study, I will explore a possibility that therapeutic interventions targeting the eCB deficit is beneficial in AD.
The role of mGluR-dependent eCB signaling in drug addiction
Activation of group-I metabotropic glutamate receptors (mGluRs), as well as the scaffolding protein Homer, play a critical role in drug addiction. Furthermore, MPEP, a specific antagonist of mGluR5, has been reported to attenuate nicotine self-administration. On the other hand, activation of CB1 receptors is also known to contribute to drug addiction through the mesolimbic dopaminergic reward pathway, and, antagonism of CB1 receptors may facilitate smoking-cessation. However, the mechanisms responsible for these effects are not well understood.
Over the past several years, I have demonstrated that activation of mGluR5 increases the production of eCB 2-AG, which may activate the presynaptic CB1 receptors. The receptor-dependent biosynthesis of 2-AG is mediated by the ? isoform of diacylglycerol lipase (DGL-?). I also found that the scaffolding protein, Homer, interacts with DGL-?, recruiting it into the mGluR signaling complex.
I am interested to continue this project to two different directions. First, I will test the hypothesis that addiction drugs such as nicotine upregulates mGluR-dependent eCB signaling, which contributes, in turn, to the addiction. I will profile the effects of addiction drug (i) on the levels of various eCB and related lipids, as well as proteins responsible for the synthesis and deactivation of eCBs, in cultures of neuronal cells; and (ii) on eCBs and the related molecules in rat brain regions after acute and chronic administration in vivo. Second, I will research the receptor-dependent molecular changes or rearrangements in the proteins constituting mGluR signaling complex. Particular interest will be given to the expressional changes in the short- as well as long-form Homer proteins and posttranslational modifications of DGL-?.
Defining the unidentified molecular components of eCB synthesis and metabolism
Although many of the proteins importantly involved in the biosynthesis, inactivation and modulation of eCBs have been characterized and their genes cloned, some of the key players still await to be molecularly identified, including the brain form(s) of N-acyl transferase (NAT) and endocannabinoid transporter. One of my long-term goals includes the cloning and characterization of such proteins. I will use a combination of biochemical methods, such as anandamide affinity column chromatography, bioinformatics and state-of-the-art mass spectrometric analysis to achieve the goal.
My unique research expertise, which ranges from protein biochemistry and molecular biology to molecular pathology of neurological disorders, qualifies me as a competent scientist who can address the role of eCBs in brain disorders.
Jung, K.M., and Kim, D.K. (2000) Purification and Characterization of a membrane-associated 48-kilodalton phospholipase A2 in leaves of bload bean. Plant Physiol, 123(3):1057-1067.
Jung, S.Y., Suh, J.H., Park, H.J., Jung, K.M., Kim, M.Y., Na, D.S., and Kim, D.K. (2000) Identification of multiple forms of membrane-associated neutral sphingomyelinase in bovine brain. J. Neurochem. 75(3):1004-1014.
Lee, H.J.*, Jung, K.-M.*, Huang, Y.Z., Bennett, L.B., Lee, J.S., Mei, L., and Kim, T.-W. (2002) Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4. J. Biol. Chem., 277(8):6318-6323. (*; Equal contribution)
Jung, K.-M., Tan, S., Landman, N., Petrova, K., Murray, S., Lewis, R., Kim, P., Kim, D.S., Ryu, S.H., Chao, M.V., and Kim, T.-W. (2003) Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor. J. Biol. Chem., 278(43):42161-42169.
Das, I., Craig, C., Funahashi, Y., Jung, K.M., Kim, T.W., Byers, R., Weng, A.P., Kutok, J.L., Aster, J.C., and Kitajewski, J. (2004) Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function. J Biol Chem., 279(29):30771-30780.
Chang, S.S., Suratwala, J., Jung, K.M., Doppelt, J.D., Zhang, H.Z., Blaine, T.A., Kim, T.W., Winchester, R.J., and Lee, F.Y. (2004) Bisphosphonates may reduce recurrence in giant cell tumor by inducing apoptosis. Clin Orthop. 426:103-109.
Jung, K.M., Mangieri, R., Stapleton, C., Kim, J., Fegley, D., Wallace, M., Mackie, K., Piomelli, D. (2005) Stimulation of endocannabinoid formation in brain slice cultures through activation of group I metabotropic glutamate receptors. Mol. Pharmacol. 68(5):1196-1202.
Jeon, H.J., Lee, D.H., Kang, M.S., Lee, M.O., Jung, K.M., Jung, S.Y., Kim, D.K. (2005) Dopamine release in PC12 cells is mediated by Ca-dependent production of ceramide via sphingomyelin pathway. J. Neurochem. 95(3):811-820.
Kang, M.S., Jeong, J.Y., Seo, J.H., Jeon, H.J., Jung, K.M., Chin, M.R., Moon, C.K., Bonventre, J.V., Jung, S.Y., Kim, D.K. (2006) Methylmercury induced toxicity is mediated by enhanced intracellular calcium through activation of phosphatidylcholine specific phospholipase C. Toxicol. Appl. Pharmacol. 216(2):206-215.
Katona, I., Urban, G.M., Wallace, M., Ledent, C., Jung, K.M., Piomelli, D., Mackie, K., Freund, T.F. (2006) Molecular composition of the endocannabinoid system at glutamatergic synapses. J. Neurosci. 26(21):5628-5637.
Jung, K.M.*, Astarita, G.*, Zhu, C., Wallace, M., Mackie, K., Piomelli, D. (2007) A key role for diacylglycerol lipase-alpha in metabotropic glutamate receptor-dependent endocannabinoid mobilization. Mol. Pharmacol. 72(3):612-621. (*; Equal contribution)
Kang, M.S., Jung, S.Y., Jung, K.M., Kim, S.K., Ahn, K.H., Kim, D.K. (2008) D609, an Inhibitor of phosphatidylcholine-specific phospholipase C, Inhibits group IV cytosolic phospholipase A(2). Mol. Cells 26(5):481-5.
|Grant||Alzheimer's Association, IIRG-08-92000, 09/01/08-08/31/11, $217,922 direct costs, Deficits in anandamide signaling underlie cognitive dysfunction in Alzheimer's Disease (Role: P.I.)|
2001-present, Society for Neuroscience
Assistant Project Scientist
UC Irvine 2004—2009
|Link to this profile||http://www.faculty.uci.edu/profile.cfm?faculty_id=5617|