细胞核中视黄酸介导的磷脂酶A2信号传导

Retinoic acid-mediated phospholipase A2 signaling in the nucleus.

作者信息

Farooqui Akhlaq A, Antony Pierre, Ong Wei-Yi, Horrocks Lloyd A, Freysz Louis

机构信息

Department of Molecular and Cellular Biochemistry, The Ohio State University, 1645 Neil Ave, Columbus, OH 43210, USA.

出版信息

Brain Res Brain Res Rev. 2004 Jul;45(3):179-95. doi: 10.1016/j.brainresrev.2004.03.002.

DOI:10.1016/j.brainresrev.2004.03.002

PMID:15210303

Abstract

Retinoic acid modulates a wide variety of biological processes including proliferation, differentiation, and apoptosis. It interacts with specific receptors in the nucleus, the retinoic acid receptors (RARs). The molecular mechanism by which retinoic acid mediates cellular differentiation and growth suppression in neural cells remains unknown. However, retinoic acid-induced release of arachidonic acid and its metabolites may play an important role in cell proliferation, differentiation, and apoptosis. In brain tissue, arachidonic acid is mainly released by the action of phospholipase A2 (PLA2) and phospholipase C (PLC)/diacylglycerol lipase pathways. We have used the model of differentiation in LA-N-1 cells induced by retinoic acid. The treatment of LA-N-1 cells with retinoic acid produces an increase in phospholipase A2 activity in the nuclear fraction. The pan retinoic acid receptor antagonist, BMS493, can prevent this increase in phospholipase A2 activity. This suggests that retinoic acid-induced stimulation of phospholipase A2 activity is a retinoic acid receptor-mediated process. LA-N-1 cell nuclei also have phospholipase C and phospholipase D (PLD) activities that are stimulated by retinoic acid. Selective phospholipase C and phospholipase D inhibitors block the stimulation of phospholipase C and phospholipase D activities. Thus, both direct and indirect mechanisms of arachidonic acid release exist in LA-N-1 cell nuclei. Arachidonic acid and its metabolites markedly affect the neurite outgrowth and neurotransmitter release in cells of neuronal and glial origin. We propose that retinoic acid receptors coupled with phospholipases A2, C and D in the nuclear membrane play an important role in the redistribution of arachidonic acid in neuronal and non-nuclear neuronal membranes during differentiation and growth suppression. Abnormal retinoid metabolism may be involved in the downstream transcriptional regulation of phospholipase A2-mediated signal transduction in schizophrenia and Alzheimer disease (AD). The development of new retinoid analogs with diminished toxicity that can cross the blood-brain barrier without harm and can normalize phospholipase A2-mediated signaling will be important in developing pharmacological interventions for these neurological disorders.

摘要

维甲酸可调节多种生物学过程，包括增殖、分化和凋亡。它与细胞核中的特定受体——维甲酸受体（RARs）相互作用。维甲酸介导神经细胞分化和生长抑制的分子机制尚不清楚。然而，维甲酸诱导的花生四烯酸及其代谢产物的释放可能在细胞增殖、分化和凋亡中起重要作用。在脑组织中，花生四烯酸主要通过磷脂酶A2（PLA2）和磷脂酶C（PLC）/二酰基甘油脂肪酶途径释放。我们使用了维甲酸诱导LA-N-1细胞分化的模型。用维甲酸处理LA-N-1细胞会导致核部分中磷脂酶A2活性增加。全反式维甲酸受体拮抗剂BMS493可阻止磷脂酶A2活性的这种增加。这表明维甲酸诱导的磷脂酶A2活性刺激是一个维甲酸受体介导的过程。LA-N-1细胞核也具有受维甲酸刺激的磷脂酶C和磷脂酶D（PLD）活性。选择性磷脂酶C和磷脂酶D抑制剂可阻断磷脂酶C和磷脂酶D活性的刺激。因此，LA-N-1细胞核中存在花生四烯酸释放的直接和间接机制。花生四烯酸及其代谢产物显著影响神经元和神经胶质来源细胞的神经突生长和神经递质释放。我们提出，在分化和生长抑制过程中，与核膜中的磷脂酶A2、C和D偶联的维甲酸受体在花生四烯酸在神经元和非核神经元膜中的重新分布中起重要作用。异常的类视黄醇代谢可能参与精神分裂症和阿尔茨海默病（AD）中磷脂酶A2介导的信号转导的下游转录调控。开发毒性降低、能无害穿过血脑屏障并能使磷脂酶A2介导的信号正常化的新型类视黄醇类似物，对于开发针对这些神经疾病的药物干预措施将具有重要意义。