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PubMed1998

Effect of psychosine on mitochondrial function.

The effect of psychosine on the rate of respiration at different segments of the electron transport chain, respiratory control ratio and the efficiency of phosphorylation was studied. The transfer of electrons through site I, site II and site III was studied independently. The transfer through site I and site III was inhibited by psychosine, whereas the transfer through site II was not inhibited. Cardiolipin, which is essential for the electron transfer through site I and III, was implicated to be responsible for the inhibition of electron transfer by psychosine. Electron carriers of site II are not sensitive to cardiolipin, so psychosine could not inhibit the electron transfer through this site. The ADP/O ratio and respiratory control ratio were inhibited by psychosine showing that it has an uncoupler like effect. Mitochondria isolated from rat liver, kidney and brain behaved essentially the same way in their response to psychosine. Cytochrome c oxidase was significantly inhibited by psychosine and the degree of inhibition was almost same in mitochondria and sub mitochondrial particles. The preence of outer membrane in mitochondria did not make any difference with respect to the action of psychosine on electron transport chain. Psychosine interacts at site I and site III and a change in the lipid environment of the membrane is responsible for the mitochondrial dysfunctions induced by psychosine. This represents a possible mechanism for the destruction of cells in Gaucher's and Krabbe's disease.

Animals↗

PubMed2003

Molecular mechanism of psychosine-induced cell death in human oligodendrocyte cell line.

This study delineates the molecular mechanism underlying psychosine-induced oligodendroglial cell death. An immortalized human oligodendroglial cell line, MO3.13, was treated with exogenous psychosine (beta-galactosylsphingosine), a toxic metabolite that accumulates in the tissues of patients with Krabbe's disease. The mode of cell death induced by psychosine was found to be apoptotic, as revealed by different apoptotic markers viz., TUNEL, DNA fragmentation and caspase cleavage/activation. The action of psychosine was redox sensitive, as measured by changes in mitochondrial membrane potential (psidelta), and this effect of psychosine could be reversed by pre-treatment with the antioxidant molecules N-acetyl-l-cysteine or pro-cysteine. Psychosine directly affects the mitochondria as revealed by the activation of caspase 9 but not caspase 8. Up-regulation of the c-jun/c-jun N-terminal kinase pathway by psychosine leads to the induction of AP-1 and, at the same time, psychosine also down-regulates the lipopolysaccharide-induced NF-kappaB transactivation. These observations indicate that the mechanism of action of psychosine is, through the up-regulation of AP-1, a pro-apoptotic pathway as well as, through the down-regulation of the NF-kappaB pathway, an antiapoptotic pathway.

Antioxidants↗

PubMed1993

Effects of psychosine (galactosylsphingosine) on the survival and the fine structure of cultured Schwann cells.

The cytotoxicity of psychosine (galactosylsphingosine) for cultured rat Schwann cells was studied by maintaining them in medium containing 1, 10, 50, 75 and 100 microM psychosine for 24, 48 and 72 hours (h). When incubated in 50-100 microM concentrations of psychosine for 24 h, 52-99% of cultured Schwann cells did not survive. Lower concentrations (1-10 microM) did not significantly reduce Schwann cell numbers for the first 24 h. However, only 43-69% of cultured Schwann cells survived in these low concentrations for 48 h, and substantially fewer remained after 72 h of incubation. During incubations in psychosine, bipolar processes of Schwann cells retracted; the resulting oval and rounded Schwann cells still were S-100 positive. When these Schwann cells were transferred into normal medium, their processes elongated quickly. When examined with the electron microscope, the cytoplasm of Schwann cells incubated in psychosine contained numerous membranous inclusions and fewer mitochondria, some of which were swollen. There also were fewer profiles of granular endoplasmic reticulum and some had widely dilated cisternae. These results suggest that 1) exogenous psychosine in concentrations of 1 microM and greater is cytotoxic for cultured rat Schwann cells; 2) psychosine has reversible toxic effects and its turnover is rapid; and 3) psychosine produces membranous inclusions and abnormalities in the mitochondria and granular endoplasmic reticulum of cultured Schwann cells. Our findings support the hypothesis that the accumulation of psychosine in human and murine globoid cell leukodystrophy is toxic for Schwann cells, produces changes in their capacity to maintain myelin, and leads to Schwann cell dysfunction.

Animals↗

PubMed2005

Peroxisomal participation in psychosine-mediated toxicity: implications for Krabbe's disease.

Psychosine (galactosylsphingosine) accumulation in globoid cell leukodystrophy (Krabbe's disease) results in the loss of myelin and oligodendrocytes. To understand the role of psychosine toxicity in Krabbe's disease, we examined the effects of psychosine on peroxisomal functions and their relationship with reactive oxygen species. Rat C(6) glial cells were treated with psychosine with and without cytokines. Peroxisomal beta-oxidation was significantly inhibited and very long chain fatty acid levels and free radicals were increased in treated cells. Furthermore, psychosine treatment decreased glutathione and ATP levels, plasmalogen content, and expression of alkyl-DHAP synthase. Brain tissue of twitcher mice (animal model of Krabbe's) had decreased beta-oxidation activity, low glutathione, and reduced plasmalogens. Psychosine treatment of rat primary oligodendrocytes inhibited peroxisomal activities. Psychosine-mediated loss of peroxisomal function and free radical production was inhibited with the antioxidant N-acetylcysteine in glial cells. Our results suggest that inhibition of peroxisomal functions and increased free radical production by psychosine may be partly responsible for oligodendrocyte and myelin loss observed in the Krabbe's brain, and that antioxidant therapy may be useful in the treatment of Krabbe's disease.

Adenosine Triphosphate↗

PubMed1997

Physicochemical characterization of psychosine by 1H nuclear magnetic resonance and electron microscopy.

Krabbe's disease is an autosomal recessive disease that affects the lysosomal enzyme galactosylceramidase. The storage of one of its substrates, psychosine (beta-galactosyl-sphingosine), is thought to be responsible for the induction of pathological changes. Psychosine has a free amine group which is necessary for the mediation of its toxic effects. In the present study, the physicochemical properties of psychosine were investigated. Nuclear magnetic resonance (NMR) detected pH titration was used to determine that the amine group had a pKa of 7.18 +/- 0.05. Pulsed-field gradient NMR spectroscopy was used to determine that the diffusion coefficient of 2.8 mM psychosine in D2O at pD 4.46 or 7.04 is 1.16 +/- 0.02 x 10(-10) m2/s or 0.77 +/- 0.02 x 10(-10) m2/s, respectively. Negative staining electron microscopy (EM) studies of acidic and neutral solutions of psychosine also were performed. At pH 4.5, spherical structures were formed, which were relatively stable between 3, 120, and 216 h following preparation; the diameter ranged from approximately 14 nm at the earliest time point to approximately 18 nm at the last time point. The critical micelle concentration (CMC) was 1.26 mM at pH 4.0. At pH 7.1, the structures changed from spherical structures with a diameter of 15-23 nm, at the earliest time point, to a heterogeneous population of structures ranging from spherical structures, with a diameter of only a few nm, to irregularly shaped oblong structures that had one or more dimensions exceeding 100 nm. The NMR and EM data indicate that the deprotonation of the amine group causes psychosine to form aggregates that are unstable, which prevents a determination of the CMC at a neutral pH. These data indicate that molecular interactions of psychosine at the acidic pH of the lysosome, where it is normally digested, are more orderly than those at the pH of the cytoplasm or extracellular space where psychosine goes during disease.

Diffusion↗

PubMed1993

Kinetics of inhibition of purified and mitochondrial cytochrome c oxidase by psychosine (beta-galactosylsphingosine).

1. Psychosine (beta-galactosylsphingosine) is the toxic agent in Krabbe's disease (globoid cells leukodystrophy). It inhibits purified bovine heart mitochondrial cytochrome c oxidase; there is a rapid phase of inhibition (complete within 10-15 s) and a slower phase (complete within 10-15 min). Both phases are also seen in rat liver mitochondria. IC50 is about 200 microM psychosine in the purified enzyme and less than 20 microM in mitochondria. Psychosine inhibition is due to binding to cytochrome oxidase, not cytochrome c. 2. Bovine heart submitochondrial particles show inhibition similar to rat liver mitochondria. However, although proteoliposomes containing bovine heart cytochrome oxidase show an identical fast phase, they have no noticeable slow phase of inhibition. Addition of phospholipid liposomes to submitochondrial particles relieved the majority of psychosine inhibition, consistent with the removal of those molecules binding in the slow phase. Psychosine can inhibit cytochrome oxidase molecules facing in either direction in proteoliposomes and submitochondrial particles, suggesting that it can rapidly interact with both sides of a membrane when added externally. 3. At high ionic strength, the presence of psychosine decreases the Vmax. of cytochrome oxidase with little effect on the Km for cytochrome c. This non-competitive inhibition suggests that the psychosine-enzyme complex is kinetically inactive and not labile over the time course of the assay. Psychosine does not inhibit the reduction of haem a or haem a3 by artificial electron donors, but does inhibit the reduction of haem a by cytochrome c.

Animals↗

PubMed2006

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death.

Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by the pathogenomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme galactocerebroside beta-galactosidase. This study underscores the mechanism of action of psychosine in the regulation of oligodendrocyte cell death via the generation of lysophosphatidylcholine (LPC) and arachidonic acid (AA) by the activation of secretory phospholipase A2 (sPLA2). There was a significant increase in the level of LPC, indicating a phospholipase A2 (PLA2)-dependent pathobiology, in the brains of Krabbe disease patients and those of twitcher mice, an animal model of Krabbe disease. In vitro studies of the treatment of primary oligodendrocytes and the oligodendrocyte MO3.13 cell line with psychosine also showed the generation of LPC and the release of AA in a dose- and time-dependent manner, indicating psychosine-induced activation of PLA2. Studies with various pharmacological inhibitors of cytosolic phospholipase A2 and sPLA2 and psychosine-mediated induction of sPLA2 enzymatic activity in media supernatant suggest that psychosine-induced release of AA and generation of LPC is mainly contributed by sPLA2. An inhibitor of sPLA2, 7,7-dimethyl eicosadienoic acid, completely attenuated the psychosine-mediated accumulation of LPC levels, release of AA, and generation of reactive oxygen species, and blocked oligodendroyte cell death, as evident from cell survival, DNA fragmentation, and caspase 3 activity assays. This study documents for the first time that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting demyelination in Krabbe disease.

Animals↗

PubMed1981

The effects of psychosine upon growth of human skin fibroblasts from patients with globoid cell leukodystrophy.

[3H]Thymidine incorporation into cultured skin fibroblasts from patients with globoid cell leukodystrophy (GLD) and from control individuals was utilized to monitor the effects of psychosine (galactosylsphingosine) upon cell replication. The concentration of psychosine necessary to inhibit 50% (ID50) of the growth of cultured skin fibroblasts was approximately 15 microgram/ml for both normal and GLD fibroblasts deficient in the enzyme galactosylceramide beta-galactosidase. Growth inhibition curves for GLD and for control fibroblasts were comparable after 3 days and after 7 days exposure to the glycolipid, so that accumulation of psychosine was not a critical factor affecting toxicity. Galactosylceramide, the major substrate for the enzyme galactosylceramide beta-galactosidase, did not inhibit [3H]thymidine incorporation into either normal or GLD fibroblasts at the concentration tested, in contrast to the highly toxic effects of psychosine at similar concentrations. The comparable inhibitory levels of psychosine in control cells and in GLD fibroblasts which are deficient in ability to hydrolyze this glycolipid suggest that the toxicity of psychosine is nonspecific. Therefore, these results are not consistent with the concept that globoid cell leukodystrophy is primarily a psychosine lipidosis.

Adult↗

PubMed2004

Psychosine-induced apoptosis in a mouse oligodendrocyte progenitor cell line is mediated by caspase activation.

Globoid cell leukodystrophy (GLD) is an inherited neurological disorder caused by the deficiency of galactocerebrosidase (GALC) activity resulting in cell death of oligodendrocytes and subsequent demyelination. The death of oligodendrocytes is accompanied by accumulation of psychosine, which is also a substrate for the GALC enzyme. In this report, we investigated the mechanism of the toxic effect of psychosine in a mouse-derived oligodendrocyte progenitor cell line (OLP-II), a precursor to the cell type most affected in GLD. Psychosine caused cytotoxicity in a dose-dependent manner. Lower concentration of psychosine (5 microM) did not significantly reduce OLP-II cell numbers. However, 50 microM psychosine induced up to 45% cell death. These results were confirmed by the Tunel assay, which is a hallmark for the detection of apoptosis. Moreover, psychosine treatment resulted in the activation/cleavage of initiator caspase-8 and -9, and effector caspase-3. These results support a role for psychosine in OLP-II cell death via an apoptotic mechanism, and suggest the involvement of caspases.

Animals↗

PubMed2002

Apoptotic positive cells in Krabbe brain and induction of apoptosis in rat C6 glial cells by psychosine.

Globoid cell leukodystrophy (GLD) is an autosomal recessive disorder of infants, caused by deficient activity of cerebroside-beta-galactosidase resulting in loss of myelin accompanied by loss of oligodendrocytes. The loss of oligodendrocyte population is accompanied by accumulation of psychosine, which is considered as the molecule responsible for the observed pathophysiology of GLD. We were able to detect apoptotic cells by terminal dUTP nick-end labeling assay and nuclear localization of p53 in postmortem brain tissue of Krabbe's disease patients, which were not detected in the control brain. To study the role of psychosine in cell death, we investigated the effect of psychosine on C6 glial cell survival by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Similar to ceramide (43.8% loss) the galactopsychosine and glucopsychosine treatment killed up to 46.3 and 48.75% of cells, respectively. On the other hand, sphingosine had no effect. DNA laddering assay confirmed these results. Moreover, psychosine-induced detection of annexin-V positive cells supports a role for psychosine in C6 glial cell death via the apoptotic pathway. These results indicate that psychosine may play a role in apoptotic cell loss observed in GLD brain.

Animals↗

PubMed1987

Hematopoietic cell transplantation in murine globoid cell leukodystrophy (the twitcher mouse): effects on levels of galactosylceramidase, psychosine, and galactocerebrosides.

Hematopoietic cell transplantation (HCT) prolongs survival in the twitcher mouse, an authentic animal model of human globoid cell leukodystrophy (Krabbe disease; galactosylceramidase deficiency), but the effects of HCT on levels of galactosylceramidase, psychosine, and cerebrosides in the tissues of twitcher mice have not been previously studied. Galactosylceramidase was less than 8% of control activity in tissues of untreated twitcher mice but reached normal values in brain and spleen and 20-30% of control in kidney of 100-day-old twitchers that received HCT at age 10 days. Using a recently developed method for the simultaneous determination of psychosine and cerebrosides, we measured the tissue levels of these lipids in the above animals. The levels of psychosine in brain, sciatic nerve, and kidney of untreated twitcher mice were 44, 200, and 12 times control values, respectively, in 30-day-old animals and 69, 500, and 14 times control levels in 40-day-old mice. On the other hand, levels of cerebroside were approximately 35% of control values in sciatic nerve, remained about the same in the brain, and were elevated 10-fold in the kidney of twitcher mice. After HCT, psychosine levels in the brains of 30-day-old twitchers were lowered to 30-35% of values in untreated twitchers, and the levels remained in that range during the post-HCT period. Similarly, brain cerebroside levels remained low in HCT-treated twitcher mice. Although psychosine levels in sciatic nerves of HCT-treated twitcher mice increased more slowly than in the nerves of untreated twitchers, the levels in 100-day-old HCT-treated twitcher mice had reached the same high values as those seen in untreated 40-day-old twitchers. It is not known whether the extremely high levels of psychosine in sciatic nerves ultimately contribute to the death of twitcher mice after HCT.

Aging↗

PubMed2002

Galactosylsphingosine (psychosine)-induced expression of cytokine-mediated inducible nitric oxide synthases via AP-1 and C/EBP: implications for Krabbe disease.

Globoid cell leukodystrophy (Krabbe disease) is characterized by the accumulation of a toxic metabolite, psychosine (galactosylsphingosine), which is a substrate for the deficient enzyme (galactocerebroside beta-galactosidase). This study underscores the possible role of psychosine in the effect of inducible nitric oxide synthase (iNOS) -derived NO in the pathophysiology of this demyelinating disease. For the first time, we provide evidence of the expression of iNOS in CNS of Krabbe patient and show that the iNOS-expressing cells in the CNS were astrocytes. Psychosine potentiated the LPS-induced production of proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) in primary rat astrocytes and regulated the cytokine-mediated production of NO in C6 glioma and primary rat astrocyte. Psychosine induced cytokine-mediated nuclear translocation of AP-1 and C/EBP by potentiating the expression of Fra-1 and C/EBP-delta proteins. This suggests that psychosine maintained or sustained the cytokine-primed expression of iNOS by further potentiating the nuclear translocation of AP-1 and C/EBP without modulating the cytokine-mediated transcription activity of NF-kappaB. This study hypothesizes that accumulated psychosine leads to production of cytokines and iNOS expression. The ensuing excessive production of NO and ONOO- may play a role in pathogenesis of Krabbe disease.

Animals↗

PubMed1982

Accumulation of glucosylceramide and glucosylsphingosine (psychosine) in cerebrum and cerebellum in infantile and juvenile Gaucher disease.

Three major clinical variants of Gaucher disease have been defined: Type I, chronic nonneuronopathic; Type II, acute neuronopathic; and Type III, subacute neuronopathic. In a search for the underlying molecular basis of the neurological manifestations, the concentration and composition of cholesterol, phospholipids, neutral glycosphingolipids, and gangliosides were examined in cerebral and cerebellar cortices of five cases of Type II, eight cases of Type III, and one case of presumed Type I/III. In Type II the concentration of glucosylceramide was 140-530 mumol/kg in cerebral cortex and 51-450 mumol/kg in cerebellar cortex, the highest values found in the most fulminant cases. These concentrations were 20-80 times greater than normal in cerebral cortex and 5-40 times normal in cerebellar cortex. In type III the concentration of glucosylceramide was 37-65 and 59-1750 mumol/kg in cerebral and cerebellar cortex, respectively. The highest concentrations were found in the cerebellum of patients who had survived splenectomy for several years. The ceramide composition of the accumulated glucosylceramide suggested that brain gangliosides were the major precursors of the glucosylceramide in brains of Type II but in cerebellar cortex in Type III was partly of extracerebral origin. The levels of lactosylceramide and oligohexaosylceramides were slightly raised in all brain specimens from the Gaucher cases. The ganglioside concentration was normal, whereas there was a certain increase in the proportion of GM2 and GM3 gangliosides. The brain glycosphingolipid changes in the Type I/III case were similar but slightly less than those in Type III cases of corresponding age. Glucosylsphingosine (psychosine), never detected in normal human brain, was demonstrated in brains from all the Gaucher cases. The psychosine concentration was highest in Type II cases, 3.8-8.8 and 3.9-12.3 mumol/kg in cerebral and cerebellar cortex, respectively, with the highest values found in the most fulminant cases. In type III the psychosine concentration varied more widely, 0.8-4.6 and 1.4-6.3 mumol/kg in cerebral and cerebellar cortex, respectively. The lowest value, 0.7 mumol/kg, was found in the Type I/III case. Our method detected psychosine down to 0.01 mumol/kg, which means that the concentration of psychosine was increased at least 100- to 1000-fold in Gaucher grey matter. We suggest that the accumulation of the cell-toxic substance psychosine is the basis for the extensive neuronal cell loss in Gaucher disease, which is most striking in Type II disease.

Adolescent↗

PubMed1997

Tissue culture model of Krabbe's disease: psychosine cytotoxicity in rat oligodendrocyte culture.

Krabbe's disease (globoid cell leukodystrophy) is a progressive cerebral degenerative disease of infancy characterized by severe myelin loss and the presence of globoid bodies in the white matter. Previous studies have suggested that psychosine is the causative agent for the pathogenesis of Krabbe's disease. In the present study, we investigated psychosine-induced injury and cell death of oligodendrocytes in enriched cultures of oligodendrocytes prepared from 3-week-old rat brain. The psychosine concentration sufficient to induce 50% cell death in oligodendrocytes was 30 micrograms/ml in the medium containing serum and 10 micrograms/ml in the serum-free medium. When oligodendrocytes were exposed to psychosine in the presence of phorbol esters, insulin, insulin-like growth factor I (IGF-I), demethylsulfoxide, or serum albumin, the survival of oligodendrocytes was greatly increased. These results indicate that psychosine cytotoxicity against oligodendrocytes is blocked by phorbol esters, insulin, and IGF-I through activation of protein kinase-C, by dimethylsulfoxide through activation of beta-galactosidase, and by albumin through its binding to psychosine.

Albumins↗

PubMed1990

Psychosine cytotoxicity in rat neural cell cultures and protection by phorbol ester and dimethyl sulfoxide.

In Krabbe's disease (globoid cell leukodystrophy), galactosylsphingosine (psychosine) is considered to be a causative agent of the pathology found in the nervous system of the patients. In our study, we examined the cytotoxic effect of psychosine in neural cell cultures derived from the rat nervous system. The concentration of toxic thresholds varied from cell type to cell type. The 50% of toxic doses for oligodendrocytes, astrocytes, and the sensory neurons of the dorsal root ganglia were 8, 20, and 30 micrograms/mL, respectively. Oligodendrocytes, therefore, appeared to show a higher sensitivity to psychosine than did astrocytes or neurons. When phorbol ester or DMSO was applied simultaneously with psychosine as protective agents in enriched cultures of rat oligodendrocytes, the total number of live cells and galactocerebroside-positive cells and the 2'3'-cyclic nucleotide 3'-phosphohydrolase activity in these cultures were considerably higher as compared with their levels in the experimental cultures treated with psychosine alone. These results indicate that phorbol ester and DMSO could serve as protective agents for psychosine neurotoxicity.

Animals↗

PubMed1989

[Psychosine: a "toxin" produced in the brain--its mechanism of action].

Psychosine (galactosylsphingosine) is enzymatically synthesized from UDP-galactose and sphingosine and degraded by galactosylceramidase. Galactosylceramidase is genetically deficient in Krabbe disease (globoid cell leukodystrophy) and psychosine accumulates in the brain of humans, dogs or mice affected by the disease. Psychosine has a very potent inhibitory effect on cytochrome c oxidase (COX) in mitochondria. When COX is purified, psychosine does not suppress the enzyme activity. However, a clear inhibitory effect is seen when the enzyme is "reconstituted" with sonicated phosphatidylcholine, suggesting that the inhibition of the enzymatic activity is caused by perturbation of the environment of COX in the mitochondrial membrane. Studies using analogues suggest that the free amino group in the sphingosine moiety plays an important role in exerting the effects of psychosine. The effects of psychosine are not only potent but fast and reversible. It is noteworthy that a powerful inhibitor of cellular respiration is synthesized in mammals' brain, an organ vulnerable to hypoxia.

Animals↗

PubMed1992

Plasmalopsychosine, a novel plasmal (fatty aldehyde) conjugate of psychosine with cyclic acetal linkage. Isolation and characterization from human brain white matter.

Through a systematic examination of basic (cationic) lipids separated on Folch's lower phase from extracts of human brain by cation exchange chromatography on carboxymethyl Sephadex in a chloroform/methanol mixture, followed by successive chromatographies on Florisil and Iatrobeads columns, five compounds of basic lipids were separated. Two major unknown compounds A and B and a minor unknown compound C were separated, in addition to minor compounds sphingosine and N,N-dimethylsphingosine. This paper describes the isolation and chemical characterization of major unknown compounds A and B, which were found only in the white matter but not in the gray matter of the human brain. Unmodified psychosine (galactosylsphingosine) was essentially undetectable under the experimental conditions. Unknown compounds A and B were identified as novel plasmal (fatty aldehyde) conjugates of psychosine with cyclic acetal linkage at the galactosyl residue of psychosine. Fatty aldehydes were identified as mainly palmital (16:0) and stearal (18:0). Sphingosine was identified as d18:1 sphingosine. Faster migrating compound A had 3,4-cyclic acetal linkage, and slower migrating compound B had 4,6-cyclic acetal linkage (where m is 14 or 16 and n is 12) as shown below. [formula: see text] Preliminary studies showed that compounds A, B, and C had a weak inhibitory effect on protein kinase C (PKC) and had no cytotoxic effect. In contrast, psychosine displayed a strong cytotoxicity and inhibitory effect on PKC. Therefore, the process controlling the addition or deletion of plasmal cyclic linkage to psychosine could be a crucial step in regulation of PKC, src, or other kinases susceptible to psychosine.

Acetals↗

PubMed2004

TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor.

T cell death-associated gene 8 (TDAG8) has been reported to be a receptor for psychosine. Ovarian cancer G-protein-coupled receptor 1 (OGR1) and GPR4, G-protein-coupled receptors (GPCRs) closely related to TDAG8, however, have recently been identified as proton-sensing or extracellular pH-responsive GPCRs that stimulate inositol phosphate and cAMP production, respectively. In the present study, we examined whether TDAG8 senses extracellular pH change. In the several cell types that were transfected with TDAG8 cDNA, cAMP was markedly accumulated in response to neutral to acidic extracellular pH, with a peak response at approximately pH 7.0-6.5. The pH effect was inhibited by copper ions and was reduced or lost in cells expressing mutated TDAG8 in which histidine residues were changed to phenylalanine. In the membrane fractions prepared from TDAG8-transfected cells, guanosine 5'-O-(3-thiotriphosphate) binding activity and adenylyl cyclase activity were remarkably stimulated in response to neutral and acidic pH. The concentration-dependent effect of extracellular protons on cAMP accumulation was shifted to the right in the presence of psychosine. The inhibitory psychosine effect was also observed for pH-dependent actions in OGR1- and GPR4-expressing cells but not for prostaglandin E(2)- and sphingosine 1-phosphate-induced actions in any pH in native and sphingosine 1-phosphate receptor-expressing cells. Glucosylsphingosine and sphingosylphosphorylcholine similarly inhibited the pH-dependent action, although to a lesser extent. Psychosine-sensitive and pH-dependent cAMP accumulation was also observed in mouse thymocytes. We concluded that TDAG8 is one of the proton-sensing GPCRs coupling to adenylyl cyclase and psychosine, and its related lysosphingolipids behave as if they were antagonists against protein-sensing receptors, including TDAG8, GPR4, and OGR1.

Animals↗