TRPC1-mediated Inhibition of 1-Methyl-4-phenylpyridinium Ion Neurotoxicity in Human SH-SY5Y Neuroblastoma Cells

entering the cell is rapidly taken up into the ER by SERCA activity with minimal diffusion in the subplasma membrane region. These studies indicate close apposition of the ER and plasma membrane at the site of SOCE (1-6). Thus, it has been suggested that ER localized in the subplasma membrane region is likely to be coupled to SOCE and that depletion of these local Ca 2ϩ stores triggers activation of SOCE. The presently proposed mechanisms for activation of SOCE suggest direct physical coupling between components in the ER and plasma membrane, generation of diffusible components, or recruitment of the SOC channel. The exact mechanism involved in regulation of SOCE as well as the molecular components of the channel(s) mediating Ca 2ϩ entry in different types of cells has not been clearly identified.Recent studies have suggested STIM1 (stromal interacting molecule 1) as a novel regulator for SOCE. STIM1, which is a Ca 2ϩ -binding protein localized diffusely in the ER, has been shown to relocate into a peripheral region of the cell in response to internal Ca 2ϩ store depletion (7,8). STIM1 displays punctate subplasma membrane localization in response to depletion of intracellular Ca 2ϩ stores, which has been reported to be causal in activation of SOCE and to define the elementary unit that is involved in SOCE. Although several studies have clearly established involvement of ER-plasma membrane junctional domains in the regulation of SOCE, the exact site of store depletion has not yet been demonstrated. Based on all of the data available presently, it is logical to propose that that since the EF-hand domain of STIM1 is localized in the lumen of the ER and STIM1 punctae involved in SOCE activation are localized in subplasma membrane Ca 2ϩ stores very close to the surface * The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

show abstract

“…Vybrant Staining Assay-Vybrant staining assay was used to evaluate apoptosis, using the method described previously (24).…”

Section: Methodsmentioning

confidence: 99%

Relocalization of STIM1 for Activation of Store-operated Ca2+ Entry Is Determined by the Depletion of Subplasma Membrane Endoplasmic Reticulum Ca2+ Store

Ong

Liu

Tsaneva-Atanasova

et al. 2007

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, although it is apparent that ER stress plays a major role in neurodegeneration, the mechanism by which these neurotoxins induce ER stress is not known. Previously we reported that transient receptor potential channel 1 (TRPC1) is critical for neuronal survival and that MPP + treatment decreases TRPC1 expression in SH-SY5Y and PC12 cells (18,19); however, the mechanism is not known.…”

Section: Introductionmentioning

confidence: 99%

Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling

et al. 2012

View full text Add to dashboard Cite

Individuals with Parkinson's disease (PD) experience a progressive decline in motor function as a result of selective loss of dopaminergic (DA) neurons in the substantia nigra. The mechanism(s) underlying the loss of DA neurons is not known. Here, we show that a neurotoxin that causes a disease that mimics PD upon administration to mice, because it induces the selective loss of DA neurons in the substantia nigra, alters Ca 2+ homeostasis and induces ER stress. In a human neuroblastoma cell line, we found that endogenous store-operated Ca 2+ entry (SOCE), which is critical for maintaining ER Ca 2+ levels, is dependent on transient receptor potential channel 1 (TRPC1) activity. Neurotoxin treatment decreased TRPC1 expression, TRPC1 interaction with the SOCE modulator stromal interaction molecule 1 (STIM1), and Ca 2+ entry into the cells. Overexpression of functional TRPC1 protected against neurotoxin-induced loss of SOCE, the associated decrease in ER Ca 2+ levels, and the resultant unfolded protein response (UPR). In contrast, silencing of TRPC1 or STIM1 increased the UPR. Furthermore, Ca 2+ entry via TRPC1 activated the AKT pathway, which has a known role in neuroprotection. Consistent with these in vitro data, Trpc1 -/-mice had an increased UPR and a reduced number of DA neurons. Brain lysates of patients with PD also showed an increased UPR and decreased TRPC1 levels. Importantly, overexpression of TRPC1 in mice restored AKT/mTOR signaling and increased DA neuron survival following neurotoxin administration. Overall, these results suggest that TRPC1 is involved in regulating Ca 2+ homeostasis and inhibiting the UPR and thus contributes to neuronal survival.

show abstract

“…Some studies showed that activation of TRPC1 by thapsigargin or carbachol decreased MPP1 neurotoxicity Thus TRPC1 may execute a neuroprotective role in dopaminergic neurons. Furthermore, TRPC1 may inhibit degenerative apoptotic signaling to provide neuroprotection against Parkinson's disease-inducing agents [334,335]. …”

Section: Parkinson's Diseasementioning

confidence: 99%

Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

View full text Add to dashboard Cite

Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

show abstract

TRPC1-mediated Inhibition of 1-Methyl-4-phenylpyridinium Ion Neurotoxicity in Human SH-SY5Y Neuroblastoma Cells

Abstract: Mammalian homologues of the

Cited by 107 publications

References 53 publications

Relocalization of STIM1 for Activation of Store-operated Ca2+ Entry Is Determined by the Depletion of Subplasma Membrane Endoplasmic Reticulum Ca2+ Store

Relocalization of STIM1 for Activation of Store-operated Ca2+ Entry Is Determined by the Depletion of Subplasma Membrane Endoplasmic Reticulum Ca2+ Store

Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling

Ion Channels as Drug Targets in Central Nervous System Disorders

Contact Info

Product

Resources

About