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Phosphatidylinositol in its membrane lipid environment: phosphatidylinositol (highlighted in cyan blue) is a negatively charged phospholipid and constitutes a minor component of phospholipids. Phosphatidylinositol is the parent compound of phosphoinositides that are located in the cytosolic side of hemi-membrane lipid-bilayers. Phosphatidylinositol consists of fatty-acyl chains (most often sn-1 – stearoyl, sn-2 – arachidonyl) embedded in the membrane lipid-bilayers, linked to a myo-inositol ring facing cytosol via a glycerol backbone.
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Phosphoinositides (PIs) are a family of phospholipids derived from phosphatidylinositol (PtdIns), whose location, synthesis, and degradation depend on specific PI kinases and phosphatases. PIs have emerged as fundamental regulators of secretory processes, such as neurotransmitter release, hormone secretion, and histamine release in allergic respons...
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... (PI) are derived from phosphatidylinositol. They consist of a long fatty-acyl chain embedded in the membrane bilayer, linked to a myo-inositol headgroup via a glycerol backbone (Fig. 1). The myo-inositol ring can be phosphorylated or de-phos- phorylated by phosphatidylinositol kinases and phosphatases on the 3 0 , 4 0 or 5 0 OH position to generate seven different isoforms (Fig. 2A, B and ...
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... Lipids have multiple structural, signalling, developmental and metabolic functions in the brain 2 . In particular, phospholipids are crucial components of the neuronal plasma and synaptic vesicle membranes, and are therefore considered to be essential for neurotransmission, synaptic plasticity and memory formation [3][4][5][6][7][8] . The vesicular trafficking underpinning these processes involves tightly regulated dynamic modulation of phospholipid membrane fluidity, curvature and surface chemistry in concert with protein/ protein and protein/lipid interactions at the pre-and postsynapse 9,10 . ...
Polyunsaturated free fatty acids (FFAs) such as arachidonic acid, released by phospholipase activity on membrane phospholipids, have long been considered beneficial for learning and memory and are known modulators of neurotransmission and synaptic plasticity. However, the precise nature of other FFA and phospholipid changes in specific areas of the brain during learning is unknown. Here, using a targeted lipidomics approach to characterise FFAs and phospholipids across the rat brain, we demonstrated that the highest concentrations of these analytes were found in areas of the brain classically involved in fear learning and memory, such as the amygdala. Auditory fear conditioning led to an increase in saturated (particularly myristic and palmitic acids) and to a lesser extent unsaturated FFAs (predominantly arachidonic acid) in the amygdala and prefrontal cortex. Both fear conditioning and changes in FFA required activation of NMDA receptors. These results suggest a role for saturated FFAs in memory acquisition.
... The underlying mechanisms include the Ca²þ-dependent binding of vesicular Syt1 to the plasma membrane PtdIns(4,5)P 2 (Fernandez-Chacon et al., 2001;Li et al., 2006). Subsequently, an alternative phosphoinositide pathway that can control exocytosis positively (via PtdIn3P) or negatively (via PtdIns(3,5)P 2 ) has been discovered (Osborne et al., 2008;Wen et al., 2012). Additionally, Syt1 regulates the neuronal polarity and axon differentiation in hippocampal neurons (Inoue et al., 2015). ...
Synaptotagmin 1 (Syt1) is an abundant and important presynaptic vesicle protein that binds Ca ²⁺ for the regulation of synaptic vesicle exocytosis. Our previous study reported its localization and function on spindle assembly in mouse oocyte meiotic maturation. The present study was designed to investigate the function of Syt1 during mouse oocyte activation and subsequent cortical granule exocytosis (CGE) using confocal microscopy, morpholinol-based knockdown and time-lapse live cell imaging. By employing live cell imaging, we first studied the dynamic process of CGE and calculated the time interval between [Ca ²⁺ ]i rise and CGE after oocyte activation. We further showed that Syt1 was co-localized to cortical granules (CGs) at the oocyte cortex. After oocyte activation with SrCl 2 , the Syt1 distribution pattern was altered significantly, similar to the changes seen for the CGs. Knockdown of Syt1 inhibited [Ca ²⁺ ]i oscillations, disrupted the F-actin distribution pattern and delayed the time of cortical reaction. In summary, as a synaptic vesicle protein and calcium sensor for exocytosis, Syt1 acts as an essential regulator in mouse oocyte activation events including the generation of Ca ²⁺ signals and CGE.
... In this sense, it is well-established that phosphatidyl inositol 4,5-bipho- sphate (PIP2) is a specific requirement for exocytosis ( Fig. 1) [26], being recruited in secretory sites by intra- cellular calcium elevations during cell stimulation [27]. Today, these initial studies have been supported by recent studies proving that PIP2 coordinates the translocation of secretory vesicles to their docking sites on the plasma membrane in a Cdc42-dependent man- ner [28,29]. In that way, forms clusters that, in addi- tion to nucleation of the formation of F-actin bundles, also interact with SNARE proteins [30], and in conse- quence act as a beacon for vesicle guidance to active secretory sites (Fig. 1). ...
Membrane fusion is a key event in exocytosis of neurotransmitters and hormones stored in intracellular vesicles. In this process, SNARE proteins are essential components of the exocytotic molecular machinery, while lipids have been seen traditionally as structural elements. However, the so‐called signalling lipids, such as sphingosine and arachidonic acid, interact with SNAREs and directly modulate the frequency and mode of fusion events. Interestingly, recent work has proved that the sphingosine analogue FTY‐720, used in the treatment of multiple sclerosis, mimics the effects of signalling lipids. In the present Review, we discuss recent investigations suggesting that endogenous signalling lipids and synthetic analogues can modulate important physiological aspects of secretion, such as quantal release, vesicle recruitment into active sites, vesicle transport and even organelle fusion in the cytosol. Therefore, these compounds are far from being merely structural components of cellular membranes. This article is protected by copyright. All rights reserved.
... This F-actin recruitment seems to be mediated throught N-WASP and the Arp2/3 complex, two factors governing actin nucleation during propulsion of secretory vesicles [54]. These initial studies have been supported by a recent work probing that glycerophospholipid phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) coordinates the translocation of secretory vesicles to their docking sites on the plasma membrane in a Cdc42-dependent manner [65,66]. PtdIns(4,5)P2 forms clusters that, in addition to nucleating the formation of F-actin, also interact with SNARE proteins [2] and act as a Bbeacon^for vesicle guidance to active sites. ...
Actin is one of the most ubiquitous protein playing fundamental roles in a variety of cellular processes. Since early in the 1980s, it was evident that filamentous actin (F-actin) formed a peripheral cortical barrier that prevented vesicles to access secretory sites in chromaffin cells in culture. Later, around 2000, it was described that the F-actin structure accomplishes a dual role serving both vesicle transport and retentive purposes and undergoing dynamic transient changes during cell stimulation. The complex role of the F-actin cytoskeleton in neuroendocrine secretion was further evidenced when it has been proved to participate in the scaffold structure holding together the secretory machinery at active sites and participate in the generation of mechanical forces that drive the opening of the fusion pore, during the first decade of the present century. The complex vision of the multiple roles of F-actin in secretion we have acquired to date comes largely from studies performed on traditional 2D cultures of primary cells; however, recent evidences suggest that these may not accurately mimic the 3D in vivo environment, and thus, more work is now needed on adrenomedullary cells kept in a more “native” configuration to fully understand the role of F-actin in regulating chromaffin granule transport and secretion under physiological conditions.
... Numerous, previous studies demonstrate a role of inositol-containing lipids (as substrates for kinases/phosphatatases) in various key regulatory functions in the brain 47 including neural development. And moreover, emerging evidence suggests a contribution to both neuroexcitatory processes 58 , and neurodegeneration 59 . Taken together with the other diverse roles of lipids in cell membrane integrity, and myelination, observed effects on lipid biosynthesis (as revealed by the present integrated metabolomics approach) point to a previously unrecognized role of these metabolic pathways with respect to the apparently multifaceted contribution of BMAA to neurodegeneration. ...
β-methylamino-L-alanine (BMAA) has been linked to several interrelated neurodegenerative diseases. Despite considerable research, specific contributions of BMAA toxicity to neurodegenerative diseases remain to be fully resolved. In the present study, we utilized state-of-the-art high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR), applied to intact zebrafish (Danio rerio) embryos, as a model of vertebrate development, to elucidate changes in metabolic profiles associated with BMAA exposure. Complemented by several alternative analytical approaches (i.e., in vivo visualization and in vitro assay), HRMAS NMR identified robust and dose-dependent effect of BMAA on several relevant metabolic pathways suggesting a multifaceted toxicity of BMAA including: (1) localized production of reactive oxygen species (ROS), in the developing brain, consistent with excitotoxicity; (2) decreased protective capacity against excitotoxicity and oxidative stress including reduced taurine and glutathione; (3) inhibition of several developmentally stereotypical energetic and metabolic transitions, i.e., metabolic reprogramming; and (4) inhibition of lipid biosynthetic pathways. Matrix-assisted laser desorption time-of-flight (MALDI-ToF) mass spectrometry further identified specific effects on phospholipids linked to both neural development and neurodegeneration. Taken together, a unified model of the neurodevelopmental toxicity of BMAA in the zebrafish embryo is presented in relation to the potential contribution of BMAA to neurodegenerative disease.
... The involvement of the lipidic environment is also extremely important during exocytosis (Di Paolo and De Camilli, 2006;Osborne et al., 2006;Wen et al., 2012). In particular, the phosphoinositide PtdIns(4,5)P 2 , which can bind and nucleate actin (Wen et al., 2011), is an important signaling lipid in both exo-and endocytic processes. ...
Bulk endocytosis allows stimulated neurons to take up a large portion of the presynaptic plasma membrane in order to regenerate synaptic vesicle pools. Actin, one of the most abundant proteins in eukaryotic cells, plays an important role in this process, but a detailed mechanistic understanding of the involvement of the cortical actin network is still lacking, in part due to the relatively small size of nerve terminals and the limitation of optical microscopy. We recently discovered that neurosecretory cells display a similar, albeit much larger, form of bulk endocytosis in response to secretagogue stimulation. This allowed us to identify a novel highly dynamic role for the acto-myosin II cortex in generating constricting rings that precede the fission of nascent bulk endosomes. In this review we focus on the mechanism underpinning this dramatic switch in the organization and function of the cortical actin network. We provide additional experimental data that suggest a role of tropomyosin Tpm3.1 and Tpm4.2 in this process, together with an emerging model of how actin controls bulk endocytosis.
... First, the reported process is dependent of F-actin-myosin II activity (Figure 1), ensuring cortical dynamics and tensional forces [29,31], and probably involves 'de novo' F-actin polymerization induced by the N-WASP and Cdc42 pathway [5,26,32]. A recent report demonstrated that the glycerophospholipid phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P 2 ] coordinates the translocation of secretory vesicles to their docking sites on the plasma membrane in a Cdc42-dependent manner [33][34][35][36] (Figure 1). PtdIns(4,5)P 2 forms clusters that, in addition to nucleating the formation of F-actin, interact with SNARE proteins [37] and act as a beacon for vesicle guidance to secretory sites [38]. ...
The cortical actin network is a tight array of filaments located beneath the plasma membrane. In neurosecretory cells, secretory vesicles are recruited on this network via a small insert isoform of myosin VI in a Ca(2+)-dependent manner. Upon secretagogue stimulation, myosin II mediates a relaxation of the actin network leading to synchronous translocation of bound or caged vesicles to the plasma membrane where they undergo exocytosis. F-actin is also recruited to secretory sites, where structural changes are detected immediately preceding and following exocytic events. Here we examine the mechanism underpinning the astonishing multifunctionality of this network in the various stages of vesicular exocytosis and compensatory bulk endocytosis. We propose a theoretical framework incorporating critical roles of the actin network in coupling these processes.
... A recent study, for instance, showed that PI3P hydrolysis to phosphatidylinositol (PI) by the lipid phosphatase MTM1 (Myotubularin 1), which is mutated in the X-linked disease centronuclear myopathy, is essential for surface delivery of endosomes and subsequent exocytosis (Ketel et al. 2016). It is thus not surprising, that deficiencies in phospholipid metabolism have been associated with impaired neuronal function and linked to neurological diseases, such as Alzheimer's disease and amyloid lateral sclerosis (Wen et al. 2012), but also to neurodevelopmental disorders including autism and schizophrenia (Gross and Bassell 2014) . The enzymes involved in phosphoinositide synthesis and hydrolysis, lipid kinases and phosphatases, are therefore of central interest to understand underlying disease mechanisms and to identify targeted treatment options. ...
Phosphoinositides are essential components of lipid membranes and crucial regulators of many cellular functions, including signal transduction, vesicle trafficking, membrane receptor localization and activity, and determination of membrane identity. These functions depend on the dynamic and highly regulated metabolism of phosphoinositides and require finely balanced activity of specific phosphoinositide kinases and phosphatases. There is increasing evidence from genetic and functional studies that these enzymes are often dysregulated or mutated in autism spectrum disorders; in particular, phosphoinositide 3-kinases and their regulatory subunits appear to be affected frequently. Examples of autism spectrum disorders with defective phosphoinositide metabolism are fragile X syndrome and autism disorders associated with mutations in the phosphoinositide 3-phosphatase tensin homolog deleted on chromosome 10 (PTEN), but recent genetic analyses also suggest that select nonsyndromic, idiopathic forms of autism may have altered activity of phosphoinositide kinases and phosphatases. Isoform-specific inhibitors for some of the phosphoinositide kinases have already been developed for cancer research and treatment, and a few are being evaluated for use in humans. Altogether, this offers exciting opportunities to explore altered phosphoinositide metabolism as a therapeutic target in individuals with certain forms of autism. This review summarizes genetic and functional studies identifying defects in phosphoinositide metabolism in autism and related disorders, describes published preclinical work targeting phosphoinositide 3-kinases in neurological diseases, and discusses the opportunities and challenges ahead to translate these findings from animal models and human cells into clinical application in humans. © 2016 Wiley Periodicals, Inc.
... Furthermore, reduction of phosphatidylinositol 3,5-bisphosphate potentiates neuroexocytosis and leads to neuronal degeneration, a mechanism that has been linked to certain forms of Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. 30 In short, the strategy of combining field investigation in highly inbred areas of Brazil, searching for of clusters of genetic disorders, with a state-of-art molecular approach proved once again to be successful. Using this approach, our group has recently identified, in a neighboring community, MED25 as another gene associated with autosomal recessive ID. 16 Now we report the identification of a novel homozygous duplication of 5 bp in IMPA1, in a large consanguineous family with nine individuals with severe ID and disruptive behavior. ...
The genetic basis of intellectual disability (ID) is extremely heterogeneous and relatively little is known about the role of autosomal recessive traits. In a field study performed in a highly inbred area of Northeastern Brazil, we identified and investigated a large consanguineous family with nine adult members affected by severe ID associated with disruptive behavior. The Genome-Wide Human SNP Array 6.0 microarray was used to determine regions of homozygosity by descent from three affected and one normal family member. Whole-exome sequencing (WES) was performed in one affected patient using the Nextera Rapid-Capture Exome kit and Illumina HiSeq2500 system to identify the causative mutation. Potentially deleterious variants detected in regions of homozygosity by descent and not present in either 59 723 unrelated individuals from the Exome Aggregation Consortium (Browser) or 1484 Brazilians were subject to further scrutiny and segregation analysis by Sanger sequencing. Homozygosity-by-descent analysis disclosed a 20.7-Mb candidate region at 8q12.3-q21.2 (lod score: 3.11). WES identified a homozygous deleterious variant in inositol monophosphatase 1 (IMPA1) (NM_005536), consisting of a 5-bp duplication (c.489_493dupGGGCT; chr8: 82,583,247; GRCh37/hg19) leading to a frameshift and a premature stop codon (p.Ser165Trpfs*10) that cosegregated with the disease in 26 genotyped family members. The IMPA1 gene product is responsible for the final step of biotransformation of inositol triphosphate and diacylglycerol, two second messengers. Despite its many physiological functions, no clinical phenotype has been assigned to this gene dysfunction to date. Additionally, IMPA1 is the main target of lithium, a drug that is at the forefront of treatment for bipolar disorder.Molecular Psychiatry advance online publication, 29 September 2015; doi:10.1038/mp.2015.150.
... Different authors demonstrated that PtdIns-3,4,5-P3 is required for these events to take place and that it is formed by phosphorylation of PtdIns-4,5-P2 by class I phosphoinositide 3-kinases [23,24]. Wen et al. [25] have also described novel aspects of neuroexocytosis. Apart from the well known role of PtdIns-4,5-P2 in the mobilization of secretory vesicles to the plasma membrane, other phosphoinositides have also been involved in this pathway. ...
Phospholipid and phosphoinositide phosphorylation pathways have been shown to be of crucial importance on producing lipid mediators. The earlier findings reported on lipid molecules playing roles in different metabolic pathways used to assign them the exclusive role of second messenger generators. Several researchers have recently described how direct interaction of phospholipids and phosphoinositides with molecules or organelles, without the need for producing second messenger molecules, is responsible for their mechanism of action. Organophosphate and or-ganochlorine pesticide toxicity mechanisms have been extensively studied in relation to their well known effects on cholinesterase activities and on the alterations of electric activity in the nervous system of different organisms respectively. There is little but consistent evidence that some compounds, including in both groups of pesticides, are also able to interact with pho-spholipid and phosphoinositide phosphorylation pathways in several organisms and tissues. The present review consists of an actualization of basic research on phospholipid and phosphoinositide phosphoryla-tion and hydrolysis pathways, as well as a description of some reported evidences for the effects of the above mentioned pesticides on them.
