Research focuses on molecular messenger systems characterized in the Snyder laboratory which are substrates for actions of drugs of abuse. One involves a signaling cascade linking nitric oxide (NO), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the ubiquitin E3-ligase Siah-1 and nuclear targets. A second deals with inositol hexakisphosphate kinase-2 (IPK6K2) in cell death and neurotoxicity, while a third addresses inositol polyphosphate multikinase (IPMK) and neural function. The NO-GAPDH-Siahl pathway was discovered as a cell death signaling system acting via nuclear p53. Recent work reveals a physiologic role wherein nitrosylated GAPDH, responding to neuronal growth factors, via Siah-1, degrades the histone methylating enzyme SUV39H1 leading to histone acetylation, gene transcription and dendritic outgrowth. Cocaine, in behavioral stimulant doses, activates this pathway. We will elucidate this pathway. IP6K2, a mediator of apoptosis, acts via p53. We are assessing how it distinguishes cell arrest/cell death via influences upon DNA protein kinase to activate p53. Its role in cocaine and MPTP actions is being investigated. IPMK is an inositol phosphate kinase and a PI3-kinase. We recently discovered that it is physiologically nitrosylated and acetylated, then binds to CBP and CREB, apparently activating CREB genetic programs. Cocaine administration activates IPMK nitrosylation/acetylation. We will explore its neural functions using newly generated IPMK knockout mice. We recentiy discovered that IPMK binds the small G-protein Rheb, known to activate mTOR. We previously showed that IPMK binds and stabilizes mTOR. We will investigate whether IPMK/Rheb coordinately regulate mTOR signaling in the brain in response to abusable drugs.

Public Health Relevance

Our research elucidates how the NO-GAPDH-Siah signaling cascade mediates neural messages including actions of cocaine. The work on IP6K2 and IPMK is similariy relevant, especially the novel potential role of nitrosylated/acetylated IPMK as a regulator of genetic programs impacted by cocaine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA000266-43
Application #
8663844
Study Section
Special Emphasis Panel (ZDA1-EXL-T)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
43
Fiscal Year
2014
Total Cost
$389,153
Indirect Cost
$148,935
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Harraz, Maged M; Snyder, Solomon H (2017) Antidepressant Actions of Ketamine Mediated by the Mechanistic Target of Rapamycin, Nitric Oxide, and Rheb. Neurotherapeutics 14:728-733
Park, Alan Jung; Havekes, Robbert; Fu, Xiuping et al. (2017) Learning induces the translin/trax RNase complex to express activin receptors for persistent memory. Elife 6:
Fu, Chenglai; Xu, Jing; Cheng, Weiwei et al. (2017) Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via ?-actinin and focal adhesion kinase. Proc Natl Acad Sci U S A 114:2036-2041
Paul, Bindu D; Snyder, Solomon H (2017) Gasotransmitter hydrogen sulfide signaling in neuronal health and disease. Biochem Pharmacol :
Dawson, Ted M; Dawson, Valina L (2017) Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics. Annu Rev Pharmacol Toxicol 57:437-454
Fu, Xiuping; Shah, Aparna; Baraban, Jay M (2016) Rapid reversal of translational silencing: Emerging role of microRNA degradation pathways in neuronal plasticity. Neurobiol Learn Mem 133:225-232
Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2016) GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 31:95-102
Rosenthal, Liana S; Drake, Daniel; Alcalay, Roy N et al. (2016) The NINDS Parkinson's disease biomarkers program. Mov Disord 31:915-23
Mills, Kelly A; Mari, Zoltan; Bakker, Catherine et al. (2016) Gait function and locus coeruleus Lewy body pathology in 51 Parkinson's disease patients. Parkinsonism Relat Disord 33:102-106
Xu, Jin-Chong; Fan, Jing; Wang, Xueqing et al. (2016) Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity. Sci Transl Med 8:333ra48

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