Regulation of phosphatidic Acid metabolism by sphingolipids in the central nervous system

Abstract

This paper explores the way ceramide, sphingosine, ceramide 1-phosphate, and sphingosine 1-phosphate modulate the generation of second lipid messengers from phosphatidic acid in two experimental models of the central nervous system: in vertebrate rod outer segments prepared from dark-adapted retinas as well as in rod outer segments prepared from light-adapted retinas and in rat cerebral cortex synaptosomes under physiological aging conditions. Particular attention is paid to lipid phosphate phosphatase, diacylglycerol lipase, and monoacylglycerol lipase. Based on the findings reported in this paper, it can be concluded that proteins related to phototransduction phenomena are involved in the effects derived from sphingosine 1-phosphate/sphingosine or ceramide 1-phosphate/ceramide and that age-related changes occur in the metabolism of phosphatidic acid from cerebral cortex synaptosomes in the presence of either sphingosine 1-phosphate/sphingosine or ceramide 1-phosphate/ceramide. The present paper demonstrates, in two different models of central nervous system, how sphingolipids influence phosphatidic acid metabolism under different physiological conditions such as light and aging.

Figure 1

Metabolic pathways of sphingolipid metabolism. Ceramide (Cer) is either sinthesized by de novo pathway through the sequential action of serine palmitoyl transferase (SPT), ketosphinganine reductase (3-KR), ceramide synthase (CerS), and dihydroceramide desaturase (DES), or it is generated from sphingomyelin (SM) hydrolisis by sphingomyelinase enzyme (SMase). Cer could be converted into sphingosine (Sph) by ceramidase (CDase) action. Ceramide kinase (CerK) and sphingosine kinase (SphK) generate ceramide 1-phosphate (C1P) and sphingosine 1-phosphate (S1P), respectively.

Figure 2

Modulation of lipid enzymatic activities by sphingolipids in two experimental models of isolated rod outer segments from vertebrate retinas under dark (DROS) and light (BLROS) conditions. Under dark condition Cer, Sph, and their phosphorylated products, S1P and C1P, diminish LPPs and DAGL activities. Under light condition, both Sph and Cer stimulate DAGL activity. These effects depend on the presence of soluble and peripherial proteins, as was observed in depleted DROS and BLROS where LPPs' inhibition produced by sphingolipids is higher than in entire ROS. Interestingly, in depleted DROS, the absence of these proteins produces an increase in DAGL activity. These results indicate that protein translocation (transducin and arrestin) between inner and outer segment or protein activation, caused by light exposure, could modulate enzymatic activities involved in PA metabolism. The relative size of arrows indicates the different degree of PA metabolism in DROS and BLROS.

Figure 3

Modulation of PA metabolic pathways by sphingolipids in synaptosomes (Syn) from adult (a) and aged (b) rat cerebral cortex. In adult Syn (a), Cer modulates DAGL and MAGL activities negatively while their phosphorylated form, C1P, stimulates MAG and Gly production via LPAPase/MAGL pathway. In aged Syn (b), results indicate that there is a major modulation by sphingolipids. Cer and Sph stimulate PA metabolization via LPPs/DAGL/MAGL pathway. C1P increases LPAPase, DAGL, and MAGL activities. In contrast, S1P inhibits DAG generation but produces an increase in Gly formation. (1) LPPs, lipid phosphate phosphatase; (2) DAGL, diacylglycerolipase; (3) MAGL, monoacylglycerolipase; (4) PLA, phospholipase A; (5) LPAPase, lysophospholipase phosphatase or LPPs. The relative size of arrows indicates the predominance of PA metabolism pathway.