当前位置： SCI文献检索 > NEUROCHEMISTRY INTERNATIONAL期刊下所有文献 > HEK-293 cells expressing the human dopamine transporter are susceptible to low concentrations of 1-methyl-4-phenylpyridine (MPP+) via impairment of energy metabolism.

HEK-293 cells expressing the human dopamine transporter are susceptible to low concentrations of 1-methyl-4-phenylpyridine (MPP+) via impairment of energy metabolism.

Abstract：

:Selective dopaminergic neurotoxicity induced by 1-methyl-4-phenylpyridine (MPP+) is believed to be due to the transmembrane uptake by the dopamine transporter and subsequent inhibition of mitochondrial complex I and/or production of free radicals. However, little is known about the molecular sequence of intracellular events leading to cell death induced by low concentrations of MPP+. Here we stably express the human dopamine transporter (hDAT) in human embryonic kidney HEK-293 cells to correlate cytotoxicity and indices of cellular energy metabolism after exposure to low concentrations of MPP+. The permanent ektopic expression of hDAT in HEK-293 cells confers time and dose-dependent cytotoxicity at nanomolar concentrations of MPP+ with an IC50 value of 740 nM after 48 h. MPP+ initially induces a fast increase of cellular NADH content within the first 6 h, followed by a slow reduction of intracellular ATP (IC50 value of 690 nM after 48 h) as well as reduction of intracellular ATP/ADP ratio. These changes of cellular energy metabolism precede reduction of cell viability. The toxic effects of MPP+ are blocked by the hDAT inhibitor GBR12909 with EC50 values of 110 and 60 nM for cytotoxicity and ATP depletion, respectively. Antioxidants such as D-alpha-tocopherol and ascorbic acid do not have significant protective effects against MPP+ toxicity. This study shows that HEK-293 cells expressing the hDAT gene are highly sensitive to MPP+ due to (i) transmembrane uptake of MPP+ by the dopamine transporter, (ii) cellular energy depletion, probably caused by inhibition of mitochondrial complex I activity and (iii) that the toxicity is independent from the presence of antioxidants. This cell system may serve as a screening system for endogenous and exogenous compounds with similar effects compared to MPP+ as well as protective agents.

journal_name

Neurochem Int

journal_title

Neurochemistry international

authors

Storch A,Ludolph AC,Schwarz J

doi

10.1016/s0197-0186(99)00083-2

subject

Has Abstract

pub_date

1999-11-01 00:00:00

pages

393-403

issue

5

eissn

0197-0186

issn

1872-9754

pii

S0197-0186(99)00083-2

journal_volume

35

pub_type

杂志文章

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