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The Effects of L- Arginine and Nitric Oxide Donors on the Induction of Mitochondrial Permeability Transition Pore by Calcium Ions and Palmitoylcarnitine. Possible Involvement of Mitochondrial NO/cGMP/PKG Signaling System
Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology ( IF 1.1 ) Pub Date : 2021-02-21 , DOI: 10.1134/s1990747820050050
V. V. Dynnik , E. V. Grishina , N. I. Fedotcheva

Abstract

This study was focused on the mechanisms of the protective effects of L-arginine and the nitric oxide donor SNAP under the induction of cyclosporine A-dependent mitochondrial permeability transition pore (MPTP) by excess of Ca2+ or D,L-palmitoylcarnitine (PC). The possible involvement of a signaling system that included mitochondrial enzymes NO-synthase (mtNOS), guanylate cyclase (GC), and cGMP-dependent protein kinase G (PKG) (mtNOS/GC/PKG-SS) in the regulation of MPTP was investigated. The experiments were performed on isolated liver mitochondria using inhibitory analysis. The results of the study have shown that L-arginine and SNAP caused a dose-dependent effects on the opening of MPTP. L‑Arginine and SNAP at low concentrations (5–100 μM) activated protective mechanisms, providing an increase in the mitochondrial calcium buffer capacity (CRC) and the critical (threshold) concentration of palmitoylcarnitine (PC*) required for MPTP induction. At higher concentrations, L-arginine (more than 500 μM) and SNAP (more than 100 μM) caused the opposite effect, that is, they suppressed respiration and promoted pore opening. Inhibitors of NOS, GC, and PKG eliminated the protective effects observed at low concentrations of L‑arginine and SNAP. The experiments conducted with a specific inhibitor of inducible NOS (W1400) showed that this calcium-independent enzyme did not participate in the regulation of MPTP in our experiments. Based on the results obtained, it can be assumed that the calcium-dependent mitochondrial signaling system mtNOS/GC/PKG-SS is involved in the regulation of MPTP, providing an increase in CRC and PC*. At high concentrations of L-arginine or SNAP, excess of NO overcame the protection provided by mtPKG and promoted pore opening.



中文翻译:

L-精氨酸和一氧化氮供体对钙离子和棕榈酰肉碱诱导线粒体通透性转变孔的影响。线粒体NO / cGMP / PKG信号系统可能参与其中

摘要

这项研究的重点是在过量的Ca 2+DL-棕榈酰肉碱(PC )诱导的环孢素A依赖性线粒体通透性转化孔(MPTP)诱导下L-精氨酸和一氧化氮供体SNAP的保护作用机理。)。研究了包括线粒体酶NO合酶(mtNOS),鸟苷酸环化酶(GC)和依赖cGMP的蛋白激酶G(PKG)(mtNOS / GC / PKG-SS)的信号传导系统可能的参与。使用抑制分析对分离的肝线粒体进行实验。研究结果表明,L-精氨酸和SNAP对MPTP的开放具有剂量依赖性。大号‑低浓度(5–100μM)的精氨酸和SNAP激活了保护机制,从而增加了线粒体钙缓冲容量(CRC)和诱导MPTP所需的棕榈酰肉碱(PC *)的临界浓度(阈值)。在更高的浓度下,L-精氨酸(大于500μM)和SNAP(大于100μM)产生相反的作用,即它们抑制了呼吸作用并促进了孔的开放。NOS,GC和PKG抑制剂消除了在低浓度L下观察到的保护作用-精氨酸和SNAP。用诱导型NOS的特异性抑制剂(W1400)进行的实验表明,该钙依赖性酶在我们的实验中不参与MPTP的调节。根据获得的结果,可以假定钙依赖性线粒体信号传导系统mtNOS / GC / PKG-SS参与了MPTP的调节,从而增加了CRC和PC *。在高浓度的L-精氨酸或SNAP下,过量的NO克服了mtPKG提供的保护作用并促进了开孔。

更新日期:2021-02-22
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