Phospholipid signaling during stramenopile development

Development of sessile organisms requires adaptation to an ever-changing environment. In order to respond quickly to these challenges, complex signaling mechanisms have evolved to facilitate cellular modifications. The importance of phospholipid-based signaling pathways in plants, as well as animals, has recently been gaining attention. Both the PLD and PLC pathways produce the signaling molecule PA, which modulates MTs, F-actin and endomembrane trafficking. We have examined the roles of the PLD signaling pathway during development of the marine brown alga Silvetia compressa. Zygotes were treated with 1- and 2-butanol, both of which activate the PLD enzyme. However, only 1-butanol competes with water as a transphosphatidylation substrate, at the expense of PA production. Interestingly, we found that 1- and 2-butanol both disrupted MT organization and thereby cell division, with 1-butanol being more potent. These findings question whether the effects of butyl alcohol treatment are due to lowered PA levels or activation of the PLD enzyme. Additionally, preliminary results show that inhibition of DAGK results in loss of centrosomal MTs and formation of cortical MT cages that are strikingly similar to those formed following 1-butanol treatment. These data suggest that perturbation of the PLD or PLC pathway leads to cortical stabilization and/or nucleation of MT arrays.Key words: actin, brown algae, cytoskeleton, development, endomembrane, microtubule, phosphatidic acid, phospholipase C, phospholipase D, stramenopile     

Investigation of the potential involvement of eicosanoid metabolites in anti-diuretic hormone signaling in Rhodnius prolixus

The use of naturally occurring plant-derived compounds for controlling insect pests remains an attractive alternative to potentially dangerous synthetic chemical compounds. One prospective plant-based compound, isoforms of the so-called jack bean urease (JBU) from the jack bean, Canavalia ensiformis, as well a derived peptide, Jaburetox-2Ec, have insecticidal effects on an array of insect species. In the Chagas' disease vector, Rhodnius prolixus, some of the physiological effects attributed to these urease isoforms include inhibition of serotonin (5-HT)-stimulated fluid secretion by the Malpighian tubules (MTs). Here, we investigated whether the effects of these exogenous urease isoforms were targeting the neuroendocrine network involved in the anti-diuretic hormone (RhoprCAPA-2) signaling cascade. We show that pharmacological agents known to interfere with eicosanoid metabolite biosynthesis do not affect RhoprCAPA-2 inhibition of 5-HT-stimulated fluid secretion by MTs. In addition, we demonstrate that RhoprCAPA-2 inhibition of MTs is independent of extracellular or intracellular calcium. Using a heterologous system for analysis of receptor activation, we show that neither JBU nor Jaburetox-2Ec are agonists of the anti-diuretic hormone receptor, RhoprCAPAr1. Finally, activation of the receptor using sub-maximal doses of the natural ligand, RhoprCAPA-2, was not influenced by the presence of either JBU or Jaburetox-2Ec indicating that the urease isoforms do not compete with RhoprCAPA-2 for binding and activation of RhoprCAPAr1. Taken together, these results suggest that at least two distinct mechanisms leading to inhibition of fluid secretion by MTs exist in R. prolixus and, unlike the urease-related effects, the eicosanoid metabolite pathway is not involved in RhoprCAPA-2 mediated anti-diuresis.     

Neuregulin signaling, cortical circuitry development and schizophrenia

Neuregulin-1 (Nrg1) and its receptor ErbB4 are encoded by genes that have been repeatedly linked to schizophrenia. Both genes are thought to play important roles in the development of brain circuitry, but their precise contribution to the disease process remains unknown. In this review, we summarize novel findings on the biological function of Nrg1 and ErbB4 in mice, with a focus on the development of inhibitory circuits in the cerebral cortex. We will also discuss how this basic knowledge may help us to understand the etiology of schizophrenia, and eventually lead to the development of novel therapies for treating the disorder.     

Parasitosis, dopaminergic modulation and metabolic disturbances in schizophrenia: evolution of a hypothesis

Recent meta-analyses have provided a comprehensive overview of studies investigating Toxoplasma gondii antibodies in schizophrenic patients, thus attempting to clarify the potential role these infections might play in causing schizophrenia. Issues for further research have been suggested. Associations and theories that may enrich the current level of knowledge with regard to this significant subject deserve attention. Anti-parasitic agents as well as antipsychotics are effective in treating parasitosis. Both classes of drugs have been shown to exert dopaminergic activity. Parasites and human organisms have a long history of mutual contact. The effect of parasitosis on the host and the host's response to infection are undoubtedly the product of a long evolutionary process. The neurochemical background of delusions of parasitosis is potentially similar to ancient evolutionary traces of altered neurotransmission and neuropeptide gene expression caused by parasites; these include fungal and viral infections. This is very unique in medicine if a class of drugs is effective in the treatment of an illness but also cures the delusion of the same disorder as well. Furthermore, metabolic disturbances such as hyperglycemia and insulin resistance were reported several decades before the antipsychotic era. Toxoplasmosis may also be linked to insulin resistance. Schizophrenia research can benefit from understanding this evolutionary link. New chemical entities that are liable to alter neurochemical changes related to the brain's perception of the risk of predation secondary to parasites may result in new approaches for the treatment of psychosis. These findings suggest that further research is needed to clarify this evolutionary link between parasite infection and delusions of parasitosis. We believe this model may well open up new avenues of research in the discovery of drugs to counteract schizophrenia.     

Opiate, cannabinoid, and eicosanoid signaling converges on common intracellular pathways nitric oxide coupling.

Scientific fields as they emerge initially appear to be unrelated to other projects even if they are in a similar area of interest. This is especially true in the case of opiate, cannabinoid, and eicosanoid signaling processes. In this limited speculative review, we attempt to examine aspects of their intracellular cascading signaling systems for their commonalities. We find intracellular calcium mobilization, nuclear factor kappa B involvement, adenylate cyclase activity, and, finally, constitutive nitric oxide release to be converging points for these signaling processes, occurring by separate and distinct receptor-mediated effector systems. Phosphokinase C, mitogen activated protein kinase, and cytosolic phospholipase A2 also represent points of common impact. In this regard, aspirin also appears to be involved in an aspect of this signaling convergence. We conclude that many of the physiological observations regarding the actions of these signaling molecules, for example, immunosuppression, neurotransmission, vasodilation, cellular adherence, and cytotoxicity, can now be understood by considering their converging biochemical cascades.     

Association study between monoamine oxidase A (MAOA) gene polymorphisms and schizophrenia: lack of association with schizophrenia and possible association with affective disturbances of schizophrenia

Monoamine oxidase A (MAOA) catalyzes monoamine neurotransmitters including dopamine, 5-hydroxytryptamine (5-HT, serotonin), and norepinephrine. MAOA also plays a key role in emotional regulation. The aim of this study was to investigate the associations between the exonic single nucleotide polymorphisms (SNPs) of the MAOA gene located on the X chromosome and schizophrenia. We also analyzed the relationships between these SNPs and the common clinical symptoms of schizophrenia such as persecutory delusion, auditory hallucinations, affective disturbances, and poor concentration. Two hundred seventy five Korean schizophrenia patients and 289 control subjects were recruited. Three SNPs [rs6323 (Arg294Arg), rs1137070 (Asp470Asp), and rs3027407 (3′-untranslated region)] of the MAOA gene were selected and genotyped by direct sequencing. The common clinical symptoms of schizophrenia according to the Operation Criteria Checklist were analyzed. Three examined SNPs showed no associations with male and female schizophrenia, respectively (p > 0.05). In the analysis of the common clinical symptoms of schizophrenia patients, three examined SNPs were associated with affective disturbances, especially restricted affect and blunted affect in male schizophrenia, respectively (restricted affect, p = 0.002, OR = 2.71, 95 % CI 1.45–5.00; blunted affect, p = 0.009, OR 2.25, 95 % CI 1.22–4.12). The SNPs were not associated with other clinical symptoms of schizophrenia (persecutory delusion, auditory hallucinations, and poor concentration). These results suggest that exonic SNPs (rs6323, rs1137070, and rs3027407) of the MAOA gene may be contributed to affective disturbances of Korean males schizophrenia, especially restricted affect and blunted affect.     

Dysregulation of neural calcium signaling in Alzheimer disease,bipolar disorder and schizophrenia

Neurons have highly developed Ca²⁺ signaling systems responsible for regulating a large number of neural functions such as the control of brain rhythms, information processing and the changes in synaptic plasticity that underpin learning and memory. The tonic excitatory drive, which is activated by the ascending arousal system, is particularly important for processes such as sensory perception, cognition and consciousness. The Ca²⁺ signaling pathway is a key component of this arousal system that regulates the neuronal excitability responsible for controlling the neural brain rhythms required for information processing and cognition. Dysregulation of the Ca²⁺ signaling pathway responsible for many of these neuronal processes has been implicated in the development of some of the major neural diseases in man such as Alzheimer disease, bipolar disorder and schizophrenia. Various treatments, which are known to act by reducing the activity of Ca²⁺ signaling, have proved successful in alleviating the symptoms of some of these neural diseases.     

Phospholipid membrane composition affects EGF receptor and Notch signaling through effects on endocytosis during Drosophila development

The role of phospholipids in the regulation of membrane trafficking and signaling is largely unknown. Phosphatidylcholine (PC) is a main component of the plasma membrane. Mutants in the Drosophila phosphocholine cytidylyltransferase 1 (CCT1), the rate-limiting enzyme in PC biosynthesis, show an altered phospholipid composition with reduced PC and increased phosphatidylinositol (PI) levels. Phenotypic features of dCCT1 indicate that the enzyme is not required for cell survival, but serves a role in endocytic regulation. CCT1- cells show an increase in endocytosis and enlarged endosomal compartments, whereas lysosomal delivery is unchanged. As a consequence, an increase in endocytic localization of EGF receptor (Egfr) and Notch is observed, and this correlates with a reduction in signaling strength and leads to patterning defects. A further link between PC/PI content, endocytosis, and signaling is supported by genetic interactions of dCCT1 with Egfr, Notch, and genes affecting endosomal traffic.     

Brain-derived neurotropic factor/TrkB signaling in the pathogenesis and novel pharmacotherapy of schizophrenia

The role of neurotropins, predominantly brain-derived neurotropic factor (BDNF), has been implicated in the pathophysiology as well as treatment outcome of schizophrenia. Both human and rodent studies indicate that the beneficial effects of antipsychotic drugs are mediated, at least in part, through BDNF and its receptor, TrkB. This review will discuss the available data on the levels of BDNF and TrkB in subjects with schizophrenia and in animals with and without conventional antipsychotics. The data concerning the impact of the antipsychotic drugs on BDNF/TrkB signaling will also be discussed. More importantly, this review will provide future perspective on BDNF/TrkB signaling as a novel molecular target to correct the pathogenesis and improve the long-term clinical outcome by treatments with conventional and adjunctive drugs.     

Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia

How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders.     

Cryptotanshinone reverses reproductive and metabolic disturbances in prenatally androgenized rats via regulation of ovarian signaling mechanisms and androgen synthesis

This trial explores 1) prenatally androgenized (PNA) rats as a model of polycystic ovary syndrome (PCOS) and 2) reproductive and metabolic effects of cryptotanshinone in PNA ovaries. On days 16-18 of pregnancy, 10 rats were injected with testosterone propionate (PNA mothers) and 10 with sesame oil (control mothers). At age 3 mo, 12 female offspring from each group were randomly assigned to receive saline and 12 cryptotanshinone treatment during 2 wk. Before treatment, compared with the 24 controls, the 24 PNA rats had 1) disrupted estrous cycles, 2) higher 17-hydroxyprogesterone (P = 0.030), androstenedione (P = 0.016), testosterone and insulin (P values = 0.000), and glucose (P = 0.047) levels, and 3) higher areas under the curve (AUC) for glucose (AUC-Glu, P = 0.025) and homeostatic model assessment for insulin resistance (HOMA-IR, P = 0.008). After treatment, compared with vehicle-treated PNA rats, cryptotanshinone-treated PNA rats had 1) improved estrous cycles (P = 0.045), 2) reduced 17-hydroxyprogesterone (P = 0.041), androstenedione (P = 0.038), testosterone (P = 0.003), glucose (P = 0.036), and insulin (P = 0.041) levels, and 3) lower AUC-Glu (P = 0.045) and HOMA-IR (P = 0.024). Western blot showed that cryptotanshinone reversed the altered protein expressions of insulin receptor substrate-1 and -2, phosphatidylinositol 3-kinase p85α, glucose transporter-4, ERK-1, and 17α-hydroxylase within PNA ovaries. We conclude that PNA model rats exhibit reproductive and metabolic phenotypes of human PCOS and that regulation of key molecules in insulin signaling and androgen synthesis within PNA ovaries may explain cryptotanshinone's therapeutic effects.     

Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia

Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia. Among NRG1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in the modulation of N-methyl-D-aspartate (NMDA) receptor signaling. Here, using a new postmortem tissue-stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia. Levels of NRG1 and erbB4, however, did not differ between schizophrenia and control groups. To evaluate possible causes for this hyperactivation of erbB4 signaling, we examined the association of erbB4 with PSD-95 (postsynaptic density protein of 95 kDa), as this association has been shown to facilitate activation of erbB4. Schizophrenia subjects showed substantial increases in erbB4-PSD-95 interactions. We found that NRG1 stimulation suppresses NMDA receptor activation in the human prefrontal cortex, as previously reported in the rodent cortex. NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects than in controls, consistent with enhanced NRG1-erbB4 signaling seen in this illness. Therefore, these findings suggest that enhanced NRG1 signaling may contribute to NMDA hypofunction in schizophrenia.     

Phospholipid metabolism and prolactin secretion in vitro

The possible mechanisms by which phospholipid metabolism may be involved in the biochemical events underlying pituitary hormone secretion in basal and stimulated conditions were examined. Particular emphasis was given to the role of changes in the turnover of specific membrane phospholipids, the polyphosphoinositides, in the stimulatory effect of TRH and neurotensin on prolactin release in vitro. Finally, some comments on the involvement of arachidonate and/or its metabolites in the mechanisms of release of the hormone have been reported. In this respect, the possibility that a specific diacylglycerol lipase may represent a link between the 'phosphatidylinositol effect' and the production of arachidonate from mammotroph membranal phospholipids was examined using the rather selective inhibitor of diacylglycerol lipase RHC80267.     

Phospholipid Involvement in Frost Tolerance

Changes in frost tolerance and in phospholipid content were studied in the leaves of winter rape plants (Brassica napus L. var. oleifera L. cv. Górczański) grown under natural or artificially controlled conditions. Frost hardening was found to be a three-stage process. During the first stage, occurring at low but above freezing environmental temperatures, phospholipid changes do not seem to be directly related to the leaf frost tolerance. This stage of hardening is possibly related to a metabolic shift caused by the cessation of growth. The achievement of the second level of frost tolerance in the fully turgid leaves depends on the occurrence of sub-freezing temperature and is related to increase in phospholipid level. It was shown that freezing brought about phospholipid degradation which was reversible only in slightly injured leaves with a relatively high phospholipid content. The third stage of hardening is related to frost-induced dehydration of the cells and may overlap the second one.