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Annual Review of Physiology Feb 2024Transient receptor potential (TRP) ion channels have diverse activation mechanisms including physical stimuli, such as high or low temperatures, and a variety of... (Review)
Review
Transient receptor potential (TRP) ion channels have diverse activation mechanisms including physical stimuli, such as high or low temperatures, and a variety of intracellular signaling molecules. Regulation by phosphoinositides and their derivatives is their only known common regulatory feature. For most TRP channels, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] serves as a cofactor required for activity. Such dependence on PI(4,5)P has been demonstrated for members of the TRPM subfamily and for the epithelial TRPV5 and TRPV6 channels. Intracellular TRPML channels show specific activation by PI(3,5)P. Structural studies uncovered the PI(4,5)P and PI(3,5)P binding sites for these channels and shed light on the mechanism of channel opening. PI(4,5)P regulation of TRPV1-4 as well as some TRPC channels is more complex, involving both positive and negative effects. This review discusses the functional roles of phosphoinositides in TRP channel regulation and molecular insights gained from recent cryo-electron microscopy structures.
Topics: Humans; Transient Receptor Potential Channels; Phosphatidylinositols; Cryoelectron Microscopy
PubMed: 37871124
DOI: 10.1146/annurev-physiol-042022-013956 -
Clinical Immunology (Orlando, Fla.) Nov 2023Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies (aPLs), which can lead to thrombosis and pregnancy...
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies (aPLs), which can lead to thrombosis and pregnancy complications. Within the diverse range of aPLs, anti-phosphatidylserine/prothrombin antibodies (aPS/PT) have gained significance in clinical practice. The detection of aPS/PT has proven valuable in identifying APS patients and stratifying their risk, especially when combined with other aPL tests like lupus anticoagulant (LA) and anti-β-glycoprotein I (aβGPI). Multivariate analyses have confirmed aPS/PT as an independent risk factor for vascular thrombosis and obstetric complications, with its inclusion in the aPL score and the Global Anti-Phospholipid Syndrome Score (GAPSS) aiding in risk evaluation. However, challenges remain in the laboratory testing of aPS/PT, including the need for assay standardization and its lower sensitivity in certain patient populations. Further research is necessary to validate the clinical utility of aPS/PT antibodies in APS diagnosis, risk stratification, and management.
Topics: Female; Pregnancy; Humans; Antiphospholipid Syndrome; Prothrombin; Phosphatidylserines; Antibodies, Antiphospholipid; beta 2-Glycoprotein I; Thrombosis
PubMed: 37838215
DOI: 10.1016/j.clim.2023.109804 -
Planta Oct 2023The phosphatidic acid phosphohydrolase of Marchantia polymorpha modulates plastid glycolipid synthesis through the ER pathway and is essential for normal plant...
Phosphatidic acid phosphohydrolase modulates glycerolipid synthesis in Marchantia polymorpha and is crucial for growth under both nutrient-replete and -deficient conditions.
The phosphatidic acid phosphohydrolase of Marchantia polymorpha modulates plastid glycolipid synthesis through the ER pathway and is essential for normal plant development regardless of nutrient availability. Membrane lipid remodeling is one of the strategies plant cells use to secure inorganic phosphate (Pi) for plant growth, but many aspects of the molecular mechanism and its regulation remain unclear. Here we analyzed membrane lipid remodeling using a non-vascular plant, Marchantia polymorpha. The lipid composition and fatty acid profile during Pi starvation in M. polymorpha revealed a decrease in phospholipids and an increase in both galactolipids and betaine lipids. In Arabidopsis thaliana, phosphatidic acid phosphohydrolase (PAH) is involved in phospholipid degradation and is crucial for tolerance to both Pi and nitrogen starvation. We produced two M. polymorpha PAH (MpPAH) knockout mutants (Mppah-1 and Mppah-2) and found that, unlike Arabidopsis mutants, Mppah impaired plant growth with shorter rhizoids compared with wild-type plants even under nutrient-replete conditions. Mutation of MpPAH did not significantly affect the mole percent of each glycerolipid among total membrane glycerolipids from whole plants under both Pi-replete and Pi-deficient conditions. However, the fatty acid composition of monogalactosyldiacylglycerol indicated that the amount of plastid glycolipids produced through the endoplasmic reticulum pathway was suppressed in Mppah mutants. Phospholipids accumulated in the mutants under N starvation. These results reveal that MpPAH modulates plastid glycolipid synthesis through the endoplasmic reticulum pathway more so than what has been observed for Arabidopsis PAH; moreover, unlike Arabidopsis, MpPAH is crucial for M. polymorpha growth regardless of nutrient availability.
Topics: Marchantia; Phosphatidate Phosphatase; Arabidopsis; Fatty Acids; Membrane Lipids
PubMed: 37792042
DOI: 10.1007/s00425-023-04247-4 -
Cells Apr 2024Lysophosphatidic acid (LPA) is a phospholipid that displays potent signalling activities that are regulated in both an autocrine and paracrine manner. It can be found... (Review)
Review
Lysophosphatidic acid (LPA) is a phospholipid that displays potent signalling activities that are regulated in both an autocrine and paracrine manner. It can be found both extra- and intracellularly, where it interacts with different receptors to activate signalling pathways that regulate a plethora of cellular processes, including mitosis, proliferation and migration. LPA metabolism is complex, and its biosynthesis and catabolism are under tight control to ensure proper LPA levels in the body. In cancer patient specimens, LPA levels are frequently higher compared to those of healthy individuals and often correlate with poor responses and more aggressive disease. Accordingly, LPA, through promoting cancer cell migration and invasion, enhances the metastasis and dissemination of tumour cells. In this review, we summarise the role of LPA in the regulation of critical aspects of tumour biology and further discuss the available pre-clinical and clinical evidence regarding the feasibility and efficacy of targeting LPA metabolism for effective anticancer therapy.
Topics: Humans; Neoplasms; Signal Transduction; Cell Movement; Lysophospholipids
PubMed: 38607068
DOI: 10.3390/cells13070629 -
Bioorganic & Medicinal Chemistry Letters Nov 2023Sphingosine-1-phosphate (S1P) is a chemotactic lipid that influences immune cell positioning. S1P concentration gradients are necessary for proper egress of lymphocytes...
Sphingosine-1-phosphate (S1P) is a chemotactic lipid that influences immune cell positioning. S1P concentration gradients are necessary for proper egress of lymphocytes from the thymus and secondary lymphoid tissues. This trafficking is interdicted by S1P receptor modulators, and it is expected that S1P transporter (Spns2) inhibitors, by reshaping S1P concentration gradients, will do the same. We previously reported SLF1081851 as a prototype Spns2 inhibitor, which provided a scaffold to investigate the importance of the oxadiazole core and the terminal amine. In this report, we disclose a structure-activity relationship study by incorporating imidazole as both a linker and surrogate for a positive charge in SLF1081851. In vitro inhibition of Spns2-dependent S1P transport in HeLa cells identified 7b as an inhibitor with an IC of 1.4 ± 0.3 µM. The SAR studies reported herein indicate that imidazolium can be a substitute for the terminal amine in SLF1081851 and that Spns2 inhibition is highly dependent on the lipid alkyl tail length.
Topics: Humans; HeLa Cells; Lysophospholipids; Sphingosine; Imidazoles; Anion Transport Proteins
PubMed: 37832799
DOI: 10.1016/j.bmcl.2023.129516 -
American Journal of Human Genetics Aug 2023Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups...
Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] phosphatases cause a broad spectrum of neurodevelopmental disorders such as Lowe and Joubert syndromes and congenital muscular dystrophy with cataracts and intellectual disability, which are thus associated with increased levels of PI(4,5)P2. Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction. We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking. In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants.
Topics: Animals; Phosphatidylinositols; Syndrome; Actins; Zebrafish; Intellectual Disability; Phosphoric Monoester Hydrolases; Phosphatidylinositol Phosphates
PubMed: 37451268
DOI: 10.1016/j.ajhg.2023.06.012 -
Annals of Medicine Dec 2023The effect of liposomes bi-functionalized with phosphatidic acid and with a synthetic peptide derived from human apolipoprotein E has been evaluated on the aggregation...
AIM
The effect of liposomes bi-functionalized with phosphatidic acid and with a synthetic peptide derived from human apolipoprotein E has been evaluated on the aggregation features of different amyloidogenic proteins: human Amyloid β1-40 (Aβ), transthyretin (TTR) variant S52P, human β2microglobulin (β2m) variants ΔN6 and D76N, Serum Amyloid A (SAA).
METHODS
The formation of fibrillar aggregates of the proteins was investigated by ThioflavinT fluorescence assay and validated by Atomic Force Microscopy.
RESULTS
The results show that liposomes are preventing the transition of non-aggregated forms to the fibrillar state, with stronger effects on Aβ, β2m ΔN6 and SAA. Liposomes also induce disaggregation of the amyloid aggregates of all the proteins investigated, with stronger effects on Aβ, β2 D76N and TTR.SPR assays show that liposomes bind Aβ and SAA aggregates with high affinity (KD in the nanomolar range) whereas binding to TTR aggregates showed a lower affinity (KD in the micromolar range). Aggregates of β2m variants showed both high and low affinity binding sites. Computed Structural analysis of protein fibrillar aggregates and considerations on the multidentate features of liposomes allow to speculate a common mechanism of action, based on binding the β-stranded peptide regions responsible for the amyloid formation.
CONCLUSION
Thus, multifunctional liposomes perform as pharmacological chaperones with anti-amyloidogenic activity, with a promising potential for the treatment of a number of protein-misfolding diseases.Key messageAmyloidosis is a group of diseases, each due to a specific protein misfolding.Anti-amyloidogenic nanoparticles have been gaining the utmost importance as a potential treatment for protein misfolding disorders.Liposomes bi-functionalized with phosphatidic acid and with a synthetic peptide derived from human apolipoprotein E showed anti-amyloidogenic activity.
Topics: Humans; Liposomes; Amyloid; Protein Aggregates; Molecular Chaperones; Phosphatidic Acids; Apolipoproteins
PubMed: 37143345
DOI: 10.1080/07853890.2023.2205659 -
Food Chemistry Jan 2024This review explores liposomes, focusing on their structure, components, the characteristics influencing their stability and applicability in foods, and preparation... (Review)
Review
This review explores liposomes, focusing on their structure, components, the characteristics influencing their stability and applicability in foods, and preparation methods. The role of phospholipids and liposome modulators in preparing liposomes of desired structure and size is emphasized. The potential of liposomes to enhance food value through liposomal encapsulation and delivery of functional substances is reviewed. Conventional and advanced liposome preparation methods are reviewed, underscoring their impact on the marketability of liposomes. The review highlights the need for research into lecithin properties and modulators that enhance liposome stability. The need to develop cost-effective and rapid liposome preparation methods is identified as a key factor in improving the marketability of food liposomes and promoting their use in foods.
Topics: Liposomes; Phospholipids; Food; Lecithins
PubMed: 37633138
DOI: 10.1016/j.foodchem.2023.137228 -
Trends in Parasitology Feb 2024In malaria parasites, although post-translational modification of proteins with N-. O-, and C-glycosidic bond-linked glycans is limited, it is confined to relatively... (Review)
Review
In malaria parasites, although post-translational modification of proteins with N-. O-, and C-glycosidic bond-linked glycans is limited, it is confined to relatively fewer proteins in which the glycans are present at significant levels and may have important functions. Furthermore, several proteins are modified with glycosylphosphatidylinositols (GPIs) which represent the predominant glycan synthesized by parasites. Modification of proteins with GPIs is obligatory for parasite survival as GPI-anchored proteins (GPI-APs) play essential roles in all life cycle stages of the parasites, including development, egress, gametogenesis, motility, and host cell adhesion and invasion. Here, we discuss the current knowledge on the structures and potential functions of the glycan moieties of parasite proteins. The knowledge has important implications for the development of drugs and vaccines for malaria.
Topics: Animals; Glycosylation; Parasites; Plasmodium falciparum; Protein Processing, Post-Translational; Glycosylphosphatidylinositols; Polysaccharides; Protozoan Proteins
PubMed: 38262838
DOI: 10.1016/j.pt.2023.12.006 -
Biochemical Pharmacology Apr 2024Lipins are phosphatidic acid phosphatases (PAP) that catalyze the conversion of phosphatidic acid (PA) to diacylglycerol (DAG). Three lipin isoforms have been... (Review)
Review
Lipins are phosphatidic acid phosphatases (PAP) that catalyze the conversion of phosphatidic acid (PA) to diacylglycerol (DAG). Three lipin isoforms have been identified: lipin-1, -2 and -3. In addition to their PAP activity, lipin-1 and -2 act as transcriptional coactivators and corepressors. Lipins have been intensely studied for their role in regulation of lipid metabolism and adipogenesis; however, lipins are hypothesized to mediate several pathologies, such as those involving metabolic diseases, neuropathy and even cognitive impairment. Recently, an emerging role for lipins have been proposed in cancer. The study of lipins in cancer has been hampered by lack of inhibitors that have selectivity for lipins, that differentiate between lipin family members, or that are suitable for in vivo studies. Such inhibitors have the potential to be extremely useful as both molecular tools and therapeutics. This review describes the expression and function of lipins in various tissues and their roles in several diseases, but with an emphasis on their possible role in cancer. The mechanisms by which lipins mediate cancer cell growth are discussed and the potential usefulness of selective lipin inhibitors is hypothesized. Finally, recent studies reporting the crystallization of lipin-1 are discussed to facilitate rational design of novel lipin inhibitors.
Topics: Phosphatidate Phosphatase; Adipogenesis; Protein Isoforms; Phosphatidic Acids; Neoplasms; Organic Chemicals
PubMed: 38442792
DOI: 10.1016/j.bcp.2024.116106