title: TRPM2 Promotes Neurotoxin MPP+/MPTP-Induced Cell Death.
abstract: In neurons, Ca2+is essential for a variety of physiological processes that regulate gene transcription to neuronal growth and their survival. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ions (MPP+) are potent neurotoxins that selectively destroys the dopaminergic (DA) neurons and mimics Parkinson's disease (PD) like symptoms, but the mechanism as how MPP+/MPTP effects DA neuron survival is not well-understood. In the present study, we found that MPP+treatment increased the level of reactive oxygen species (ROS) that activates and upregulates the expression and function of melastatin-like transient receptor potential (TRPM) subfamily member, melastatin-like transient receptor potential channel 2 (TRPM2). Correspondingly, TRPM2 expression was also increased in substantia nigra of MPTP-induced PD mouse model and PD patients. ROS-mediated activation of TRPM2 resulted in an increased intracellular Ca2+, which in turn promoted cell death in SH-SY5Y cells. Intracellular Ca2+overload caused by MPP+-induced ROS also affected calpain activity, followed by increased caspase 3 activities and activation of downstream apoptotic pathway. On the other hand, quenching of H2O2by antioxidants, resveratrol (RSV), or N-acetylcysteine (NAC) effectively blocked TRPM2-mediated Ca2+influx, decreased intracellular Ca2+overload, and increased cell survival. Importantly, pharmacological inhibition of TRPM2 or knockdown of TRPM2 using siRNA, but not control siRNA, showed an increased protection by preventing MPP+-induced Ca2+increase and inhibited apoptosis. Taken together, we show here a novel role for TRPM2 expression and function in MPP+-induced dopaminergic neuronal cell death.
authors.affiliation: Department of Biomedical Science, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58201, USA.
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Biomedical Science, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58201, USA.
authors.forename: Pramod
authors.initials: P
authors.lastname: Sukumaran
authors.affiliation: Department of Biomedical Science, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58201, USA.
authors.forename: Senthil
authors.initials: S
authors.lastname: Selvaraj
authors.affiliation: Department of Biomedical Science, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58201, USA.
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Cilz
authors.affiliation: Department of Biomedical Science, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58201, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Schaar
authors.affiliation: Department of Biomedical Science, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58201, USA.
authors.forename: Saobo
authors.initials: S
authors.lastname: Lei
authors.affiliation: Department of Biomedical Science, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58201, USA. brij.singh@med.und.edu.
authors.forename: Brij B
authors.initials: BB
authors.lastname: Singh
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000368:Aged; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006540:Herbicides / Q000633:toxicity; D006801:Humans; D020267:MPTP Poisoning / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D050053:TRPM Cation Channels / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D006540:Herbicides; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D015655:1-Methyl-4-phenylpyridinium
keywords: Apoptosis; Calcium; MPTP/MPP+; Oxidative stress; ROS; TRPM2