The involvement of environmental heavy metals in Parkinson's disease (PD) has been suggested by epidemiologic studies; however, the mechanism of this effect is unknown. PD is characterized by the aggregation of alpha-synuclein in Lewy bodies. We previously showed that Pb2+ accelerates proteasomal activity. Therefore, we examined the effect of Pb2+, Ga3+, and Cu2+ on alpha-synuclein in human SH-SY5Y cells. The heavy metals induced an increase in heme-oxygenase-1 levels without significant cell death or ROS generation. The metals inhibited ALA-dehydratase, which is the inhibitory subunit of the proteasome, thereby accelerating proteasomal activity and decreasing protein levels of CDK-1 and PBGD. However, alpha-synuclein protein levels increased after exposure to metals, similar to the effect obtained with the proteasome inhibitor, hemin, suggesting that alpha-synuclein is inaccessible to proteasomal degradation. Indeed, electron microscopy revealed the formation of aggresomes in Pb2+- or hemin-treated cells. Thus, although heavy metals enhance proteasomal activity, alpha-synuclein is protected from degradation, and its protein levels and aggregation are increased.

1995-03-01·Biochemical and Biophysical Research Communications3区 · 生物学

Sensitizing Effect of Lysophosphatidic Acid on Mechanoreceptor-Linked Response in Cytosolic Free Ca2+ Concentration in Cultured Smooth Muscle Cells

3区 · 生物学

Article

作者: Aizawa, Hiromi ; Momose, Kazutaka ; Ohata, Hisayuki ; Nobe, Koji ; Seito, Nakako

We found that lysophosphatidic acid (LPA) sensitizes response in cytosolic free Ca2+ concentration ([Ca2+]i) to mechanical stimulation in cultured longitudinal muscle cells from guinea pig ileum. [Ca2+]i was transiently increased by spritzing of bath solution onto cells as mechanical stimulation in the presence of LPA, but not in absence of LPA. The effect was reversible and concentration-dependent (1-30 nM). Ga3+ but not nicardipine inhibited the [Ca2+]i transient in the presence of LPA. Phosphatidic acid also induced the sensitization, but the effective concentration was more than 10 times higher than in LPA. Histamine and carbachol did not have any sensitizing effect to mechanical stimulation. These results show that LPA sensitizes mechanoreceptor-linked response, suggesting that LPA may play an important role in mechanotransduction mechanisms as an endogenous regulatory factor.

1993-03-01·Investigative ophthalmology & visual science2区 · 医学

Effects of Al3+ and Be2+ ions combined with NaF on ciliary process adenylyl cyclase activity and aqueous humor dynamics in the rabbit eye.

2区 · 医学

ArticleOA

作者: Mittag, T W ; Wang, R F ; Tormay, A ; Podos, S M ; Taniguchi, T ; Severin, C ; Lee, P Y

PURPOSEThe activity of Al3+, Ga3+, and Be2+ ions in the presence of NaF to directly activate G-proteins was investigated by their potentiative effect on forskolin (FSK)-activated adenylyl cyclase in rabbit ciliary process membranes and their effects on aqueous humor dynamics in vivo.METHODSAdenylyl cyclase (AC) was determined by radiometric conversion of ATP to cAMP by the particulate fraction of rabbit ciliary processes. Intravitreal injections of sterile solutions of analytical grade salts were made into the center of the vitreous in a volume of 20 microliters. Intraocular pressure, aqueous humor flow, and uveoscleral outflow measurements were made by pneumatonometry, fluorophotometry, and fluorescein-dextran method, respectively. Outflow facility was determined by tonography in the intact eyes and by two-level constant pressure perfusion in cannulated eyes.RESULTSBoth Al3+ (EC50, 40 mumol/l) and Be2+ (EC50, 11 mumol/l) in the presence of 0.5-2 mM NaF activated the stimulatory G-protein Gs. Ga3+ was ineffective and did not antagonize the activation by Al3+. Intravitreal injections of Al3+ (1 mumol/eye) or Be2+ (0.5 or 1 mumol/eye) had no significant intraocular pressure (IOP) effect, nor did 1.5 or 3 mumol/eye of NaF, but when either cation was injected together with NaF, IOP decreased by up to 40% for up to 140 hr. At the time of maximum IOP effect (72 hr) aqueous humor flow determined by fluorophotometry was decreased in BeCl2+ NaF-treated eyes by 40% relative to BeCl2-treated eyes; however, tonographic facility of outflow was unaffected. Uveoscleral flow was also decreased by 38% in BeCl2+ NaF treated eyes.CONCLUSIONSThese findings support the hypothesis that Gs activation of ciliary process adenylyl cyclase decreases aqueous humor formation rate in rabbit eyes, and that activation of G-proteins mediates contraction of ciliary muscles causing a decrease of aqueous humor outflow via the uveoscleral route. The results suggest that G-proteins putatively involved in trabecular facility changes are less sensitive to activation by BeF3- than are other parameters of aqueous humor dynamics.

100 项与 GA3 MEP-TB 相关的药物交易

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