DOCSLIB.ORG

Cyclic Phosphatidic Acid: an Endogenous Antagonist of Pparγ

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cyclic Phosphatidic Acid: an Endogenous Antagonist of Pparγ Central Journal of Endocrinology, Diabetes & Obesity Editorial Corresponding author Tamotsu Tsukahara, Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Cyclic Phosphatidic Acid: An Daigaku, Uchinada, Ishikawa 920-0293, Japan, E-mail: [email protected] Submitted: 25 August 2013 Endogenous Antagonist of Accepted: 26 August 2013 Published: 29 August 2013 PPARg Copyright © 2013 Tsukahara et al. Tamotsu Tsukahara1*, Yoshikazu Matsuda2, Hisao Haniu3 and Kimiko Murakami- Murofushi4 OPEN ACCESS 1Department of Hematology and Immunology, Kanazawa Medical University, Japan 2Clinical Pharmacology Educational Center, Nihon Pharmaceutical University, Japan 3Department of Orthopaedic Surgery, Shinshu University School of Medicine, Japan 4Endowed Research Division of Human Welfare Sciences, Ochanomizu University, Japan Lysophospholipids (LPLs) have long been recognized as phosphatidylcholine (PC) to generate choline and bioactive membrane phospholipid metabolites. LPLs are small bioactive lipid, has been implicated in signal transduction, membrane lipid molecules that are characterized by a single carbon 10]. There are two chain and a polar head group. LPLs have been implicated in a PLD isoenzymes, PLD1 and PLD2, which are expressed in a number of pathological states and human diseases. LPLs include varietytrafficking, of tissues and cytoskeletal and cells [ 11reorganization]. We labeled [ cultured cells with lysophosphatidic acid (LPA), alkyl-glycerol phosphate (AGP), [32P]-orthophosphate for 30 min and compared that to [32P]- sphingoshine-1-phosphate, and cyclic phosphatidic acid (cPA). labeled cPA from vehicle control cells using two-dimensional thin In recent years, cPA has been reported to be a target for many layer chromatography. Furthermore, we used CHO cells stably diseases, including obesity [1], atherosclerosis [2], cancer [3], expressing PLD1 or PLD2 or catalytically inactive forms of PLD1 and pain [4]. cPA is an analog of LPA that has a 5-atom ring and PLD2 to delineate the roles of the PLDs in cPA formation. linking the phosphate to 2 of the glycerol carbon atoms. cPA is PLD2-expressing cell lines had an elevated basal level of cPA found in diverse organisms, from slime molds to humans [5]. The and higher PMA-stimulated cPA production relative to control concentration of cPA in human serum is estimated to be around wild-type (WT) cells [2 role of PLD2 activation in stimulus-coupled cPA production. In formation, adipocytic differentiation, lipid accumulation, and recent years, the physiological]. This findingand pathophysiological provides evidence functions for the 100 nM. cPA, along with PPARγ agonists, prevents neointima macrophages [2 upregulation of PPARγ-target gene transcription in mouse of peroxisome proliferator-activated receptor γ (PPARγ)2]. ligands cPA offers new therapeutic]. These findings opportunities support our to improvehypothesis the that quality cPA have been explored. In our recent work, we identified cPA as an Role of cPA in lipid signaling-related diseases ofis anpatient endogenous care. Here, antagonist we discuss of PPARγ. the current These knowledge data suggest on that the endogenous PPARγ antagonist generated by PLD2 [ pathophysiological actions of cPA and attempt to link them with Recent reports have been shown that LPA plays an important particular targets. role in the vascular system [12]. LPA is produced in serum after the activation of biochemical pathways linked to platelet Enzymatic formation of cPA 13] and rosiglitazone Murakami-Murofushi et al. [6] reported that cPA is detected (ROSI) induce neointima when applied topically within the carotidactivation. artery The PPARγ[14]. Neointimal agonists alkyl-LPA lesions [are characterized by Many of the activities of cPA have been attributed to albumin- the accumulation of cells within the arterial wall and are a in mammalian biological fluids, including human serum. prelude to atherosclerotic disease [14]. In recent reports, the cPA by autotaxin (ATX) under non-physiological conditions knockdown of 1-acyl-sn-glycerol-3-phosphate acyltransferase appearedassociated in lipid 2006 factors. [7,8]. ATX, The also first known report as ofphosphodiesterase the generation of2, 15]. AGPAT2 is a secreted enzyme important for generating the lipid signaling is located the endoplasmic reticulum membrane and converts molecule LPA [9]. ATX has lysophospholipase D activity and LPAβ (AGPAT2) to phosphatidic resulted acid in increased(PA). Mutations levels inof this cPA gene [ have been converts lysophosphatidylcholine (LPC) into LPA. The enzymatic associated with congenital generalized lipodystrophy (CGL) [16]. formation and function of cPA are poorly characterized. In Lipodystrophies, including CGL, are heterogeneous acquired or addition, the identity of the enzyme that contributes to the inherited disorders characterized by the selective loss of adipose tissue and development of severe insulin resistance. AGPAT2 is a member of a family of proteins with acyltransferase activity, anformation enzyme ofthat cPA can in generate biological cPA fluids [2]. PLD,remains which unknown. hydrolyzes In and mediates the acylation of LPA into PA [17]. Subauste et al. our recent work, we identified phospholipase D2 (PLD2) as Cite this article: Tsukahara T, Matsuda Y, Haniu H, Murakami-Murofushi K (2013) Cyclic Phosphatidic Acid: An Endogenous Antagonist of PPARg. J Endo- crinol Diabetes Obes 1(1): 1005. Tsukahara et al. (2013) Email: [email protected] Central recently reported that overexpression of AGPAT2 decreases 5. Murakami-Murofushi K, Kobayashi S, Onimura K, Matsumoto M, cPA levels [18]. Furthermore, the knockdown of AGPAT2 results Shioda M, Yoshida S, et al. Selective inhibition of DNA polymerase- in increases in the level of the saturated form of cPA 18:0 and alpha family with chemically synthesized derivatives of PHYLPA, a cPA16:0 [15 1258: 57-60. unique Physarum lysophosphatidic acid. Biochim Biophys Acta. 1995; dependent luciferase]. They also activation. assessed These the effect data ofsuggest AGPAT2 that on AGPAT2 PPARγ 6. Murakami-Murofushi K, Uchiyama A, Fujiwara Y, Kobayashi T, transactivation and found that AGPAT2 increases PPARγ- 1-7.Kobayashi S, Mukai M, et al. Biological functions of a novel lipid modulates PPARγ activity and glycerolipid levels. However, the mediator, cyclic phosphatidic acid. Biochim Biophys Acta. 2002; 1582: physiological context of these mechanisms in PPARγ signaling is still unclear. Further clarification of the PPARγ-cPA axis will et al. Carba analogs of cyclic phosphatidic acid are selective inhibitors In conclusion, we hope that we have provided interesting insights 7. Baker DL, Fujiwara Y, Pigg KR, Tsukahara R, Kobayashi S, Murofushi H, allow the synthesis of novel drugs that modulate PPARγ function. 2006; 281: 22786-93. cPA axis in various cardiovascular diseases. We expect that the of autotaxin and cancer cell invasion and metastasis. J Biol Chem. reviewsinto these presented recent advances in this inissue, elucidating which focusthe roles on ofthe the interplay PPARγ- 8. Tsuda S, Okudaira S, Moriya-Ito K, Shimamoto C, Tanaka M, Aoki J, et Chem. 2006; 281: 26081-8. useful for those interested in phospholipid biology, nuclear al. Cyclic phosphatidic acid is produced by autotaxin in blood. J Biol receptorbetween PPARγfunction, and and the their cardiovascular intersection system, with cardiovascularwill be highly pathologies. Pharmacol. 2010; 161: 241-270. 9. Tigyi G. Aiming drug discovery at lysophosphatidic acid targets. Br J ACKNOWLEDGMENTS 10. 11. ExtonCockcr JH.oft RegulationS. Signalling of roles phospholipase of mammalian D. FEBS phospholipase Lett. 2002; 531:D1 and 58-61. D2. This work was supported by research grants from the Astellas Cell Mol Life Sci. 2001; 58: 1674-1687. Foundation for Research on Metabolic Disorders (to Tamotsu 12. Schober A and Siess W. Lysophosphatidic acid in atherosclerotic Tsukahara), Takeda Science Foundation (to Tamotsu Tsukahara), Tsukahara) from the Japan Society for the Promotion of Science 13. diseases.Tsukahara Br JT, Pharmacol. Tsukahara 2012; R, 167:Yasuda 465-482. S, Makarova N, Valentine (JSPS),Grants-in-Aid and the for Princess Scientific Takamatsu Research (B)Cancer 25293274 Research (to FundTamotsu (to WJ, Allison P, et al. Different residues mediate recognition of 1-O-oleyllysophosphatidic acid and rosiglitazone in the ligand binding Kimiko Murakami-Murofushi). Chem. 2006; 281: 3398-3407. REFERENCES domain of peroxisome proliferator-activated receptor gamma. J Biol 1. Tsukahara T, Hanazawa S, Murakami-Murofushi K. Cyclic phosphatidic al. Lysophosphatidic acid induces neointima formation through 14. PPARgammaZhang C, Baker activation. DL, Yasuda J Exp S, Med. Makarova 2004; 199:N, Balazs 763-774. L, Johnson LR, et Resacid Commun. influences 2011; the 404:expression 109-14. and regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 cells. Biochem Biophys Alterations in lipid signaling underlie lipodystrophy secondary to 2. Tsukahara T, Tsukahara R, Fujiwara Y, Yue J, Cheng Y, Guo H, et al. 15. AGPAT2Subauste mutations. AR, Das AK, Diabetes. Li X, Elliot2012; B, 61: Evans 2922-2931. C, El Azzouny M, et al. Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid. Mol Cell. 2010; 39: 421-32. AM, et al. AGPAT2 is mutated in congenital generalized lipodystrophy 16. linkedAgarwal to AK,chromosome Arioglu E, 9q34. De Almeida Nat Genet. S, Akkoc2002; 31:N, Taylor21-23.
Load more

Recommended publications
  • Novel Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor Provide New Insights Into M1-Dependent Synaptic Plasticity and Receptor Signaling
    Novel allosteric modulators of the M1 muscarinic acetylcholine receptor provide new insights into M1-dependent synaptic plasticity and receptor signaling By Sean P Moran Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Neuroscience December 14, 2019 Nashville, Tennessee Approved: Sachin Patel M.D., Ph.D. Colleen Niswender, Ph.D. Danny Winder, Ph.D. P. Jeffrey Conn, Ph.D. ACKNOWLEDGMENTS Throughout my scientific career, there have been many people instrumental in my scientific journey. I would first like to thank Jeff Conn for providing a very supportive research atmosphere, for always making me laugh, for his insight and constructive criticism in our one-on-one meetings and for occasionally getting my name correct. I would also like to thank my thesis committee of Sachin Patel, Colleen Niswender and Danny Winder for their unwavering support during my time here at Vanderbilt. Additionally, I have very much enjoyed collaborating with Jerri Rook on many projects and would like to thank her for her sage behavioral pharmacology advice over the years. Also, thanks to the many members of the VCNDD including: Zixiu, Craig, Jon Dickerson, Dan Foster, Max, Nicole, Mark and Carrie who provided intellectual contributions, technical training or research support throughout my graduate career. Thank you to the many other members of the VCNDD, past and present, that have contributed to my various projects over the years. Thanks to the better half of Shames (James). I will our miss our long winded, highly pedantic and semantic discussions that occasionally touched on pharmacology topics…and thanks for making me not homeless.
    [Show full text]
  • Role of Phospholipases in Adrenal Steroidogenesis
    229 1 W B BOLLAG Phospholipases in adrenal 229:1 R29–R41 Review steroidogenesis Role of phospholipases in adrenal steroidogenesis Wendy B Bollag Correspondence should be addressed Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA, USA to W B Bollag Department of Physiology, Medical College of Georgia, Augusta University (formerly Georgia Regents Email University), Augusta, GA, USA [email protected] Abstract Phospholipases are lipid-metabolizing enzymes that hydrolyze phospholipids. In some Key Words cases, their activity results in remodeling of lipids and/or allows the synthesis of other f adrenal cortex lipids. In other cases, however, and of interest to the topic of adrenal steroidogenesis, f angiotensin phospholipases produce second messengers that modify the function of a cell. In this f intracellular signaling review, the enzymatic reactions, products, and effectors of three phospholipases, f phospholipids phospholipase C, phospholipase D, and phospholipase A2, are discussed. Although f signal transduction much data have been obtained concerning the role of phospholipases C and D in regulating adrenal steroid hormone production, there are still many gaps in our knowledge. Furthermore, little is known about the involvement of phospholipase A2, Endocrinology perhaps, in part, because this enzyme comprises a large family of related enzymes of that are differentially regulated and with different functions. This review presents the evidence supporting the role of each of these phospholipases in steroidogenesis in the Journal Journal of Endocrinology adrenal cortex. (2016) 229, R1–R13 Introduction associated GTP-binding protein exchanges a bound GDP for a GTP. The G protein with GTP bound can then Phospholipids serve a structural function in the cell in that activate the enzyme, phospholipase C (PLC), that cleaves they form the lipid bilayer that maintains cell integrity.
    [Show full text]
  • 1H HR-MAS and Genomic Analysis of Human Tumor Biopsies Discriminate Between High and Low Grade Astrocytomas Valeria Righi A,B,C, Jose M
    Research Article Received: 16 April 2008, Revised: 22 January 2009, Accepted: 22 January 2009, Published online in Wiley InterScience: 2009 (www.interscience.wiley.com) DOI:10.1002/nbm.1377 1H HR-MAS and genomic analysis of human tumor biopsies discriminate between high and low grade astrocytomas Valeria Righi a,b,c, Jose M. Rodad, Jose´ Pazd, Adele Muccib, Vitaliano Tugnolic, Gemma Rodriguez-Tarduchya, Laura Barriose, Luisa Schenettib, Sebastia´n Cerda´na* and Marı´a L. Garcı´a-Martı´na,y We investigate the profile of choline metabolites and the expression of the genes of the Kennedy pathway in biopsies of human gliomas (n ¼ 23) using 1H High Resolution Magic Angle Spinning (HR-MAS, 11.7 Tesla, 277 K, 4000 Hz) and individual genetic assays. 1H HR-MAS spectra allowed the resolution and relative quantification by the LCModel of the resonances from choline (Cho), phosphocholine (PC) and glycerophosphorylcholine (GPC), the three main components of the combined tCho peak observed in gliomas by in vivo 1H NMR spectroscopy. All glioma biopsies depicted a prominent tCho peak. However, the relative contributions of Cho, PC, and GPC to tCho were different for low and high grade gliomas. Whereas GPC is the main component in low grade gliomas, the high grade gliomas show a dominant contribution of PC. This circumstance allowed the discrimination of high and low grade gliomas by 1H HR-MAS, a result that could not be obtained using the tCho/Cr ratio commonly used by in vivo 1H NMR spectroscopy. The expression of the genes involved in choline metabolism has been investigated in the same biopsies.
    [Show full text]
  • Phospholipase D in Cell Proliferation and Cancer
    Vol. 1, 789–800, September 2003 Molecular Cancer Research 789 Subject Review Phospholipase D in Cell Proliferation and Cancer David A. Foster and Lizhong Xu The Department of Biological Sciences, Hunter College of The City University of New York, New York, NY Abstract trafficking, cytoskeletal reorganization, receptor endocytosis, Phospholipase D (PLD) has emerged as a regulator of exocytosis, and cell migration (4, 5). A role for PLD in cell several critical aspects of cell physiology. PLD, which proliferation is indicated from reports showing that PLD catalyzes the hydrolysis of phosphatidylcholine (PC) to activity is elevated in response to platelet-derived growth factor phosphatidic acid (PA) and choline, is activated in (PDGF; 6), fibroblast growth factor (7, 8), epidermal growth response to stimulators of vesicle transport, endocyto- factor (EGF; 9), insulin (10), insulin-like growth factor 1 (11), sis, exocytosis, cell migration, and mitosis. Dysregula- growth hormone (12), and sphingosine 1-phosphate (13). PLD tion of these cell biological processes occurs in the activity is also elevated in cells transformed by a variety development of a variety of human tumors. It has now of transforming oncogenes including v-Src (14), v-Ras (15, 16), been observed that there are abnormalities in PLD v-Fps (17), and v-Raf (18). Thus, there is a growing body of expression and activity in many human cancers. In this evidence linking PLD activity with mitogenic signaling. While review, evidence is summarized implicating PLD as a PLD has been associated with many aspects of cell physiology critical regulator of cell proliferation, survival signaling, such as membrane trafficking and cytoskeletal organization cell transformation, and tumor progression.
    [Show full text]
  • The Design and Synthesis of Autotaxin Inhibitors and Analogs of Lysophosphatidic Acid
    University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 5-2011 The esiD gn and Synthesis of Autotaxin Inhibitors and Analogs of Lysophosphatidic Acid Renuka Niranjan Gupte University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Chemicals and Drugs Commons, and the Pharmaceutics and Drug Design Commons Recommended Citation Gupte, Renuka Niranjan , "The eD sign and Synthesis of Autotaxin Inhibitors and Analogs of Lysophosphatidic Acid" (2011). Theses and Dissertations (ETD). Paper 112. http://dx.doi.org/10.21007/etd.cghs.2011.0121. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. The esiD gn and Synthesis of Autotaxin Inhibitors and Analogs of Lysophosphatidic Acid Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Pharmaceutical Sciences Research Advisor Duane D. Miller, Ph.D. Committee Isaac O. Donkor, Ph.D. Richard E. Lee, Ph.D. Wei Li, Ph.D. Gabor J. Tigyi, M.D., Ph.D. DOI 10.21007/etd.cghs.2011.0121 Comments Two year embargo expired May 2013 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/112 THE DESIGN AND SYNTHESIS OF AUTOTAXIN INHIBITORS AND ANALOGS OF LYSOPHOSPHATIDIC ACID A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Renuka Niranjan Gupte May 2011 Copyright © 2011 by Renuka N.
    [Show full text]
  • The Multifaceted Role of Extracellular Vesicles in Glioblastoma: Microrna Nanocarriers for Disease Progression and Gene Therapy
    pharmaceutics Review The Multifaceted Role of Extracellular Vesicles in Glioblastoma: microRNA Nanocarriers for Disease Progression and Gene Therapy Natalia Simionescu 1,2 , Radu Zonda 1, Anca Roxana Petrovici 1 and Adriana Georgescu 3,* 1 Center of Advanced Research in Bionanoconjugates and Biopolymers, “Petru Poni” Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania; [email protected] (N.S.); [email protected] (R.Z.); [email protected] (A.R.P.) 2 “Prof. Dr. Nicolae Oblu” Emergency Clinical Hospital, 2 Ateneului Street, 700309 Iasi, Romania 3 Department of Pathophysiology and Pharmacology, Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 8 B.P. Hasdeu Street, 050568 Bucharest, Romania * Correspondence: [email protected]; Tel.: +40-21-319-45-18 Abstract: Glioblastoma (GB) is the most aggressive form of brain cancer in adults, characterized by poor survival rates and lack of effective therapies. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression post-transcriptionally through specific pairing with target mes- senger RNAs (mRNAs). Extracellular vesicles (EVs), a heterogeneous group of cell-derived vesicles, transport miRNAs, mRNAs and intracellular proteins, and have been shown to promote horizon- tal malignancy into adjacent tissue, as well as resistance to conventional therapies. Furthermore, GB-derived EVs have distinct miRNA contents and are able to penetrate the blood–brain barrier. Numerous studies have attempted to identify EV-associated miRNA biomarkers in serum/plasma Citation: Simionescu, N.; Zonda, R.; and cerebrospinal fluid, but their collective findings fail to identify reliable biomarkers that can be Petrovici, A.R.; Georgescu, A.
    [Show full text]
  • Title Phospholipase D2 Promotes Disease Progression Of
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Kyoto University Research Information Repository Phospholipase D2 promotes disease progression of renal cell Title carcinoma through the induction of angiogenin Kandori, Shuya; Kojima, Takahiro; Matsuoka, Taeko; Yoshino, Author(s) Takayuki; Sugiyama, Aiko; Nakamura, Eijiro; Shimazui, Toru; Funakoshi, Yuji; Kanaho, Yasunori; Nishiyama, Hiroyuki Citation Cancer Science (2018), 109(6): 1865-1875 Issue Date 2018-06 URL http://hdl.handle.net/2433/233106 © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of Right the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Type Journal Article Textversion publisher Kyoto University Received: 2 October 2017 | Revised: 1 March 2018 | Accepted: 4 April 2018 DOI: 10.1111/cas.13609 ORIGINAL ARTICLE Phospholipase D2 promotes disease progression of renal cell carcinoma through the induction of angiogenin Shuya Kandori1 | Takahiro Kojima1 | Taeko Matsuoka1 | Takayuki Yoshino1 | Aiko Sugiyama2 | Eijiro Nakamura2 | Toru Shimazui3,4 | Yuji Funakoshi5 | Yasunori Kanaho5 | Hiroyuki Nishiyama1 1Faculty of Medicine, Department of Urology, University of Tsukuba, Tsukuba, A hallmark of clear cell renal cell carcinoma (ccRCC) is the presence of intracellular Japan lipid droplets (LD) and it is assumed that phosphatidic acid (PA) produced by phos- 2 DSK Project, Medical Innovation Center, pholipase D (PLD) plays some role in the LD formation. However, little is known Kyoto University Graduate School of Medicine, Kyoto, Japan about the significance of PLD in ccRCC.
    [Show full text]
  • A Molecular Target for an Alcohol Chain-Length Cutoff
    Article A Molecular Target for an Alcohol Chain-Length Cutoff Hae-Won Chung 1,2,†, E. Nicholas Petersen 1,2,†, Cerrone Cabanos 1,2, Keith R. Murphy 2,3,4, Mahmud Arif Pavel 1,2, Andrew S. Hansen 5, William W. Ja 2,3 and Scott B. Hansen 1,2 1 - Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA 2 - Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA 3 - Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA 4 - Program in Integrative Biology and Neuroscience, Florida Atlantic University, Jupiter, FL 33458, USA 5 - HBBiotech, BioInnovations Gateway, Salt Lake City, UT 84115, USA Correspondence to Scott B. Hansen: Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA. [email protected] https://doi.org/10.1016/j.jmb.2018.11.028 Edited by Daniel L. Minor Abstract Despite the widespread consumption of ethanol, mechanisms underlying its anesthetic effects remain uncertain. n-Alcohols induce anesthesia up to a specific chain length and then lose potency—an observation known as the “chain-length cutoff effect.” This cutoff effect is thought to be mediated by alcohol binding sites on proteins such as ion channels, but where these sites are for long-chain alcohols and how they mediate a cutoff remain poorly defined. In animals, the enzyme phospholipase D (PLD) has been shown to generate alcohol metabolites (e.g., phosphatidylethanol) with a cutoff, but no phenotype has been shown connecting PLD to an anesthetic effect. Here we show loss of PLD blocks ethanol-mediated hyperactivity in Drosophila melanogaster (fruit fly), demonstrating that PLD mediates behavioral responses to alcohol in vivo.
    [Show full text]
  • Rare Coding Variants in the Phospholipase D3 Gene Confer Risk for Alzheimer’S Disease”
    “Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease” Cruchaga C, et al. Nature. 2013 December 11 online Introduction Alzheimer’s Disease (AD) • Most common form of dementia • Estimated 5.2 million in US • Estimated overall heritability is up to 80% • Progressive memory loss and cognitive deficits http://www.nia.nih.gov/sites/default/files/02_degradingbrains_lg.jpg http://www.ph.nagasaki-u.ac.jp/lab/biotech/research-e.html Early Onset AD • Rare (est >200,000 cases in US) • Symptoms appear before age 65 (30s, 40s, 50s) • Tends to cluster within families • Mutations in APP, PSEN1, PSEN2 Late Onset AD • Inheritance follows complex pattern • APOE associated with risk (ε2, ε3, ε4) • Several genes associated with increased risk: CLU, PICALM, CR1, BIN1, ABCA7, MS4A, CD33, EPHA1, CD2AP, TREM2 PLD3 • Poorly characterized • Member of phospholipase D family • Localizes to lysosomes • PLD1 implicated in APP trafficking (Cai et al, 2006) • PLD2 implicated in AD (Oliveira et al, 2010) GWAS - Issues • Common variants, not rare variants – Small effects on LOAD risk – Usually do not have obvious functional effects • Expensive • Large population needed Exome Sequencing • Sequencing of exons only • Faster and cheaper • Fewer false positives • Greater sensitivity • Exome makes up ~1% of whole genome • Deep coverage w/ relatively few reads Hypothesis Alzheimer's disease risk is heritable and exome sequencing can identify low frequency heritable risk factors that are missed in GWAS. Experimental Design Results Interpretation(s)
    [Show full text]
  • Phospholipase D2 (PLD2) Is a Guanine Nucleotide Exchange Factor (GEF) for the Gtpase Rac2
    Phospholipase D2 (PLD2) is a guanine nucleotide exchange factor (GEF) for the GTPase Rac2 Madhu Mahankalia, Hong-Juan Penga, Karen M. Henkelsa, Mary C. Dinauerb, and Julian Gomez-Cambroneroa,1 aDepartment of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, OH 45435; and bDepartment of Pediatrics (Division of Hematology/Oncology) and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 Edited by Peter N. Devreotes, Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 21, 2011 (received for review September 7, 2011) We have discovered that the enzyme phospholipase D2 (PLD2) binds known that PA binds directly to Sos (9). All of the mechanisms directly to the small GTPase Rac2, resulting in PLD2 functioning as a that imply translocation to the membrane or membrane traf- guanine nucleotide exchange factor (GEF), because it switches Rac2 ficking that place GEF close to its effectors are complex and rely from the GDP-bound to the GTP-bound states. This effect is large on the formation of multimeric signaling proteins. enough to be meaningful (∼72% decrease for GDP dissociation and We show here that PLD2 functions as a GEF, because it 300% increase for GTP association, both with PLD2), it has a half- switches Rac2 from the GDP-bound to the GTP-bound state. time of ∼7 min, is enhanced with increasing PLD2 concentrations, There are a number of known GEFs, but none of the three families and compares favorably with other known GEFs, such as Vav-1. The of GEFs for monomeric GTPases is a phospholipase, making this PLD2-Rac2 protein–protein interaction is sufficient for the GEF func- study unique.
    [Show full text]
  • Interface of Phospholipase Activity, Immune Cell Function, and Atherosclerosis
    biomolecules Review Interface of Phospholipase Activity, Immune Cell Function, and Atherosclerosis Robert M. Schilke y, Cassidy M. R. Blackburn y , Temitayo T. Bamgbose and Matthew D. Woolard * Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA; [email protected] (R.M.S.); [email protected] (C.M.R.B.); [email protected] (T.T.B.) * Correspondence: [email protected]; Tel.: +1-(318)-675-4160 These authors contributed equally to this work. y Received: 12 September 2020; Accepted: 13 October 2020; Published: 15 October 2020 Abstract: Phospholipases are a family of lipid-altering enzymes that can either reduce or increase bioactive lipid levels. Bioactive lipids elicit signaling responses, activate transcription factors, promote G-coupled-protein activity, and modulate membrane fluidity, which mediates cellular function. Phospholipases and the bioactive lipids they produce are important regulators of immune cell activity, dictating both pro-inflammatory and pro-resolving activity. During atherosclerosis, pro-inflammatory and pro-resolving activities govern atherosclerosis progression and regression, respectively. This review will look at the interface of phospholipase activity, immune cell function, and atherosclerosis. Keywords: atherosclerosis; phospholipases; macrophages; T cells; lipins 1. Introduction All cellular membranes are composed mostly of phospholipids. Phospholipids are amphiphilic compounds with a hydrophilic, negatively charged phosphate group head and two hydrophobic fatty acid tail residues [1]. The glycerophospholipids, phospholipids with glycerol backbones, are the largest group of phospholipids, which are classified by the modification of the head group [1]. The negatively charged phosphate head forms an ionic bond with an amino alcohol. This bridges the glycerol backbone to the nitrogenous functional group (amino alcohol).
    [Show full text]
  • Supplemental Figures 04 12 2017
    Jung et al. 1 SUPPLEMENTAL FIGURES 2 3 Supplemental Figure 1. Clinical relevance of natural product methyltransferases (NPMTs) in brain disorders. (A) 4 Table summarizing characteristics of 11 NPMTs using data derived from the TCGA GBM and Rembrandt datasets for 5 relative expression levels and survival. In addition, published studies of the 11 NPMTs are summarized. (B) The 1 Jung et al. 6 expression levels of 10 NPMTs in glioblastoma versus non‐tumor brain are displayed in a heatmap, ranked by 7 significance and expression levels. *, p<0.05; **, p<0.01; ***, p<0.001. 8 2 Jung et al. 9 10 Supplemental Figure 2. Anatomical distribution of methyltransferase and metabolic signatures within 11 glioblastomas. The Ivy GAP dataset was downloaded and interrogated by histological structure for NNMT, NAMPT, 12 DNMT mRNA expression and selected gene expression signatures. The results are displayed on a heatmap. The 13 sample size of each histological region as indicated on the figure. 14 3 Jung et al. 15 16 Supplemental Figure 3. Altered expression of nicotinamide and nicotinate metabolism‐related enzymes in 17 glioblastoma. (A) Heatmap (fold change of expression) of whole 25 enzymes in the KEGG nicotinate and 18 nicotinamide metabolism gene set were analyzed in indicated glioblastoma expression datasets with Oncomine. 4 Jung et al. 19 Color bar intensity indicates percentile of fold change in glioblastoma relative to normal brain. (B) Nicotinamide and 20 nicotinate and methionine salvage pathways are displayed with the relative expression levels in glioblastoma 21 specimens in the TCGA GBM dataset indicated. 22 5 Jung et al. 23 24 Supplementary Figure 4.
    [Show full text]