TY - JOUR
T1 - TRPM2 promotes neurotoxin MPP+/MPTP-induced cell death
AU - Sun, Yuyang
AU - Sukumaran, Pramod
AU - Selvaraj, Senthil
AU - Cilz, Nicholas I.
AU - Schaar, Anne
AU - Lei, Saobo
AU - Singh, Brij B.
N1 - Publisher Copyright:
© Springer Science+Business Media New York 2016.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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- t e t r a h ydrop y r i d i n e (MPTP) and 1-meth y l - 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 H2O2 by antioxidants, resveratrol (RSV), or Nacetylcysteine (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.
AB - 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- t e t r a h ydrop y r i d i n e (MPTP) and 1-meth y l - 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 H2O2 by antioxidants, resveratrol (RSV), or Nacetylcysteine (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.
KW - Apoptosis
KW - Calcium
KW - MPTP/MPP
KW - Oxidative stress
KW - ROS
KW - TRPM2
UR - http://www.scopus.com/inward/record.url?scp=85047298238&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047298238&partnerID=8YFLogxK
U2 - 10.1007/s12035-016-0338-9
DO - 10.1007/s12035-016-0338-9
M3 - Article
C2 - 27957685
AN - SCOPUS:85047298238
SN - 0893-7648
VL - 55
SP - 409
EP - 420
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 1
ER -