Inoue A

References (12)

Title : Prenatal Exposure to Histone Deacetylase Inhibitors Affects Gene Expression of Autism-Related Molecules and Delays Neuronal Maturation - Kawanai_2016_Neurochem.Res_41_2574
Author(s) : Kawanai T , Ago Y , Watanabe R , Inoue A , Taruta A , Onaka Y , Hasebe S , Hashimoto H , Matsuda T , Takuma K
Ref : Neurochem Res , 41 :2574 , 2016
Abstract : Valproic acid (VPA) is a multi-target drug and an inhibitor of histone deacetylase (HDAC). We have previously demonstrated that prenatal exposure to VPA at embryonic day 12.5 (E12.5), but not at E14.5, causes autism-like behavioral abnormalities in male mouse offspring. We have also found that prenatal VPA exposure causes transient histone hyperacetylation in the embryonic brain, followed by decreased neuronal cell numbers in the prefrontal and somatosensory cortices after birth. In the present study, we examined whether prenatal HDAC inhibition affects neuronal maturation in primary mouse cortical neurons. Pregnant mice were injected intraperitoneally with VPA (500 mg/kg) and the more selective HDAC inhibitor trichostatin A (TSA; 500 microg/kg) at E12.5 or E14.5, and primary neuronal cultures were prepared from the cerebral cortices of their embryos. Prenatal exposure to VPA at E12.5, but not at E14.5, decreased total number, total length, and complexity of neuronal dendrites at 14 days in vitro (DIV). The effects of VPA weakened at 21 DIV. Exposure to TSA at E12.5, but not at E14.5, also delayed maturation of cortical neurons. In addition, real-time quantitative PCR revealed that the prenatal exposure to TSA decreased neuroligin-1 (Nlgn1), Shank2, and Shank3 mRNA levels and increased contactin-associated protein-like 2 mRNA level. The delay in neuronal maturation was also observed in Nlgn1-knockdown cells, which were transfected with Nlgn1 siRNA. These findings suggest that prenatal HDAC inhibition causes changes in gene expression of autism-related molecules linked to a delay of neuronal maturation.
ESTHER : Kawanai_2016_Neurochem.Res_41_2574
PubMedSearch : Kawanai_2016_Neurochem.Res_41_2574
PubMedID: 27300699

Title : Analysis of unique mutations in the LPAR6 gene identified in a Japanese family with autosomal recessive woolly hair\/hypotrichosis: Establishment of a useful assay system for LPA6 - Hayashi_2015_J.Dermatol.Sci_78_197
Author(s) : Hayashi R , Inoue A , Suga Y , Aoki J , Shimomura Y
Ref : J Dermatol Sci , 78 :197 , 2015
Abstract : BACKGROUND: Woolly hair (WH) is a hair shaft anomaly characterized by tightly-curled hair and is frequently associated with hypotrichosis. Non-syndromic forms of WH can show either autosomal dominant or recessive inheritance. The autosomal recessive form of WH (ARWH) is caused by mutations in either lipase H (LIPH) or lysophosphatidic acid receptor 6 (LPAR6) gene, encoding an LPA-producing enzyme PA-PLA1alpha and an LPA receptor LPA6, respectively. OBJECTIVE: To define the molecular basis of ARWH/hypotrichosis in a Japanese family.
METHODS: We performed mutational analysis of candidate genes and a series of expression and in vitro functional analyses, which we improved in this study, to determine the consequences resulting from the mutations identified in the family.
RESULTS: Novel compound heterozygous LPAR6 mutations were identified in the patient. One was a nonsense mutation c.756T>A (p.Tyr252*); the other was a large insertion mutation within the promoter region of LPAR6. Expression studies detected LPAR6 mRNA only from the c.756T>A allele in the patient's hair follicles, suggesting that the insertion in the other allele disrupted the LPAR6 promoter and thus led to a failure of transcription. Furthermore, an improved LPA6 functional assay developed in this study demonstrated aberrant expression and a subsequent loss of function of the p.Tyr252*-mutant protein. CONCLUSION: Through establishing a useful assay system for LPA6, our results further underscore the crucial roles of LPAR6 in hair follicle development and hair growth in humans at molecular levels.
ESTHER : Hayashi_2015_J.Dermatol.Sci_78_197
PubMedSearch : Hayashi_2015_J.Dermatol.Sci_78_197
PubMedID: 25828854

Title : A novel mutation, c.699C>G (p.C233W), in the LIPH gene leads to a loss of the hydrolytic activity and the LPA6 activation ability of PA-PLA1alpha in autosomal recessive wooly hair\/hypotrichosis -
Author(s) : Yoshizawa M , Nakamura M , Farooq M , Inoue A , Aoki J , Shimomura Y
Ref : J Dermatol Sci , 72 :61 , 2013
PubMedID: 23768866
Gene_locus related to this paper: human-LIPH

Title : The beta9 loop domain of PA-PLA1alpha has a crucial role in autosomal recessive woolly hair\/hypotrichosis -
Author(s) : Shinkuma S , Inoue A , Aoki J , Nishie W , Natsuga K , Ujiie H , Nomura T , Abe R , Akiyama M , Shimizu H
Ref : Journal of Investigative Dermatology , 132 :2093 , 2012
PubMedID: 22475755
Gene_locus related to this paper: human-LIPH

Title : Surface loops of extracellular phospholipase A(1) determine both substrate specificity and preference for lysophospholipids - Arima_2012_J.Lipid.Res_53_513
Author(s) : Arima N , Inoue A , Makide K , Nonaka T , Aoki J
Ref : J Lipid Res , 53 :513 , 2012
Abstract : Members of the pancreatic lipase family exhibit both lipase activity toward triacylglycerol and/or phospholipase A(1) (PLA(1)) activity toward certain phospholipids. Some members of the pancreatic lipase family exhibit lysophospholipase activity in addition to their lipase and PLA(1) activities. Two such enzymes, phosphatidylserine (PS)-specific PLA(1) (PS-PLA(1)) and phosphatidic acid (PA)-selective PLA(1)alpha (PA-PLA(1)alpha, also known as LIPH) specifically hydrolyze PS and PA, respectively. However, little is known about the mechanisms that determine their substrate specificities. Crystal structures of lipases and mutagenesis studies have suggested that three surface loops, namely, beta5, beta9, and lid, have roles in determining substrate specificity. To determine roles of these loop structures in the substrate recognition of these PLA(1) enzymes, we constructed a number of PS-PLA(1) mutants in which the three surface loops are replaced with those of PA-PLA(1)alpha. The results indicate that the surface loops, especially the beta5 loop, of PA-PLA(1)alpha play important roles in the recognition of PA, whereas other structure(s) in PS-PLA(1) is responsible for PS preference. In addition, beta5 loop of PS-PLA(1) has a crucial role in lysophospholipase activity toward lysophosphatidylserine. The present study revealed the critical role of lipase surface loops, especially the beta5 loop, in determining substrate specificities of PLA(1) enzymes.
ESTHER : Arima_2012_J.Lipid.Res_53_513
PubMedSearch : Arima_2012_J.Lipid.Res_53_513
PubMedID: 22172514

Title : Prevalent LIPH founder mutations lead to loss of P2Y5 activation ability of PA-PLA1alpha in autosomal recessive hypotrichosis - Shinkuma_2010_Hum.Mutat_31_602
Author(s) : Shinkuma S , Akiyama M , Inoue A , Aoki J , Natsuga K , Nomura T , Arita K , Abe R , Ito K , Nakamura H , Ujiie H , Shibaki A , Suga H , Tsunemi Y , Nishie W , Shimizu H
Ref : Hum Mutat , 31 :602 , 2010
Abstract : Autosomal recessive hypotrichosis (ARH) is characterized by sparse hair on the scalp without other abnormalities. Three genes, DSG4, LIPH, and LPAR6 (P2RY5), have been reported to underlie ARH. We performed a mutation search for the three candidate genes in five independent Japanese ARH families and identified two LIPH mutations: c.736T>A (p.Cys246Ser) in all five families, and c.742C>A (p.His248Asn) in four of the five families. Out of 200 unrelated control alleles, we detected c.736T>A in three alleles and c.742C>A in one allele. Haplotype analysis revealed each of the two mutant alleles is derived from a respective founder. These results suggest the LIPH mutations are prevalent founder mutations for ARH in the Japanese population. LIPH encodes PA-PLA(1)alpha (LIPH), a membrane-associated phosphatidic acid-preferring phospholipase A(1)alpha. Two residues, altered by these mutations, are conserved among PA-PLA(1)alpha of diverse species. Cys(246) forms intramolecular disulfide bonds on the lid domain, a crucial structure for substrate recognition, and His(248) is one amino acid of the catalytic triad. Both p.Cys246Ser- and p.His248Asn-PA-PLA(1)alpha mutants showed complete abolition of hydrolytic activity and had no P2Y5 activation ability. These results suggest defective activation of P2Y5 due to reduced 2-acyl lysophosphatidic acid production by the mutant PA-PLA(1)alpha is involved in the pathogenesis of ARH.
ESTHER : Shinkuma_2010_Hum.Mutat_31_602
PubMedSearch : Shinkuma_2010_Hum.Mutat_31_602
PubMedID: 20213768
Gene_locus related to this paper: human-LIPH

Title : Two pathways for lysophosphatidic acid production - Aoki_2008_Biochim.Biophys.Acta_1781_513
Author(s) : Aoki J , Inoue A , Okudaira S
Ref : Biochimica & Biophysica Acta , 1781 :513 , 2008
Abstract : Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) is a simple phospholipid but displays an intriguing cell biology that is mediated via interactions with G protein-coupled seven transmembrane receptors (GPCRs). So far, five GPCRs, designated LPA1-5, and, more recently, two additional GPCRs, GPR87 and P2Y5, have been identified as receptors for LPA. These LPA receptors can be classified into two families, the EDG and P2Y families, depending on their primary structures. Recent studies on gene targeting mice and family diseases of these receptors revealed that LPA is involved in both pathological and physiological states including brain development (LPA1), neuropathy pain (LPA1), lung fibrosis (LPA1), renal fibrosis (LPA1) protection against radiation-induced intestinal injury (LPA2), implantation (LPA3) and hair growth (P2Y5). LPA is produced both in cells and biological fluids, where multiple synthetic reactions occur. There are at least two pathways for LPA production. In serum or plasma, LPA is predominantly produced by a plasma enzyme called autotaxin (ATX). ATX is a multifunctional ectoenzyme and is involved in many patho-physiological conditions such as cancer, neuropathy pain, lymphocyte tracking in lymph nodes, obesity, diabetes and embryonic blood vessel formation. LPA is also produced from phosphatidic acid (PA) by its deacylation catalyzed by phospholipase A (PLA)-type enzymes. However, the physiological roles of this pathway as well as the enzymes involved remained to be solved. A number of phospholipase A1 and A2 isozymes could be involved in this pathway. One PA-selective PLA1 called mPA-PLA1alpha/LIPH is specifically expressed in hair follicles, where it has a critical role in hair growth by producing LPA through a novel LPA receptor called P2Y5.
ESTHER : Aoki_2008_Biochim.Biophys.Acta_1781_513
PubMedSearch : Aoki_2008_Biochim.Biophys.Acta_1781_513
PubMedID: 18621144
Gene_locus related to this paper: human-LIPH

Title : Structure and function of extracellular phospholipase A1 belonging to the pancreatic lipase gene family - Aoki_2007_Biochimie_89_197
Author(s) : Aoki J , Inoue A , Makide K , Saiki N , Arai H
Ref : Biochimie , 89 :197 , 2007
Abstract : Phospholipase A1 (PLA1) is an enzyme that hydrolyzes phospholipids and produces 2-acyl-lysophospholipids and fatty acids and is conserved in a wide range of organisms. Mammals have several enzymes that exhibit PLA1 activity in vitro. The extracellular PLA1s include phosphatidylserine (PS)-specific PLA1 (PS-PLA1), membrane-associated phosphatidic acid (PA)-selective PLA1s (mPA-PLA1alpha and mPA-PLA1beta), hepatic lipase (HL), endothelial lipase (EL) and pancreatic lipase-related protein 2 (PLRP2), all of which belong to the pancreatic lipase gene family. The former three PLA1s differ from other members in their substrate specificities, structural features and gene organizations, and form a subfamily in the pancreatic lipase gene family. PS-PLA1, mPA-PLA1alpha and mPA-PLA1beta exhibit only PLA1 activity, while HL, EL and PLRP2 show triacylglycerol-hydrolyzing activity in addition to PLA1 activity. The tertiary structures of lipases have two surface loops, the lid and the beta9 loop. The lid and the beta9 loop cover the active site in its closed conformation. An alignment of amino acid sequences of the pancreatic lipase gene family members revealed two molecular characteristics of PLA1s in the two surface loops. First, lipase members exhibiting PLA1 activity (PS-PLA1, mPA-PLA1alpha and mPA-PLA1beta, EL, guinea pig PLRP2 and PLA1 from hornet venom (DolmI)) have short lids. Second, PS-PLA1, mPA-PLA1alpha, mPA-PLA1beta and DolmI, which exhibit only PLA(1) activity, have short beta9 loops. Thus, the two surface loops appear to be involved in the ligand recognition. PS-PLA1 and mPA-PLA1s specifically hydrolyze PS and PA, respectively, producing their corresponding lysophospholipids. Lysophosphatidylserine and lysophosphatidic acid have been defined as lipid mediators with multiple biological functions. Thus, these PLA1s have a role in the production of these lysophospholipid mediators.
ESTHER : Aoki_2007_Biochimie_89_197
PubMedSearch : Aoki_2007_Biochimie_89_197
PubMedID: 17101204

Title : An improved physical and genetic map of the genome of alkaliphilic Bacillus sp. C-125 - Takami_1999_Extremophiles_3_21
Author(s) : Takami H , Nakasone K , Hirama C , Takaki Y , Masui N , Fuji F , Nakamura Y , Inoue A
Ref : Extremophiles , 3 :21 , 1999
Abstract : Among alkaliphilic bacteria reported so far, Bacillus sp. C-125 is the strain most thoroughly characterized physiologically, biochemically, and genetically. A physical map of the chromosome of this strain was constructed to facilitate further genome analysis, and the genome size was revised from 3.7 to 4.25Mb. Complete digestion of the chromosomal DNA with two rare cut restriction endonucleases, AscI and Sse8387I, each yielded 20 fragments ranging in size from 20 to 600 kb. Seventeen linking clones were isolated in each instance to join the adjacent AscI or Sse8387I fragments in the chromosomal map. All AscI linking clones isolated were sequenced and analyzed by comparison with the BSORF database to map the genes in the chromosome of strain C-125. Several ORFs showing significant similarities to those of B. subtilis in the AscI linking clones were positioned on the physical map. The oriC region of the C-125 chromosome was identified by southern blot analysis with a DNA probe containing the gyrB region.
ESTHER : Takami_1999_Extremophiles_3_21
PubMedSearch : Takami_1999_Extremophiles_3_21
PubMedID: 10086841

Title : Lamina-specific connectivity in the brain: regulation by N-cadherin, neurotrophins, and glycoconjugates - Inoue_1997_Science_276_1428
Author(s) : Inoue A , Sanes JR
Ref : Science , 276 :1428 , 1997
Abstract : In the vertebrate brain, neurons grouped in parallel laminae receive distinct sets of synaptic inputs. In the avian optic tectum, arbors and synapses of most retinal axons are confined to 3 of 15 laminae. The adhesion molecule N-cadherin and cell surface glycoconjugates recognized by a plant lectin are selectively associated with these "retinorecipient" laminae. The lectin and a monoclonal antibody to N-cadherin perturbed laminar selectivity in distinct fashions. In contrast, neurotrophins increased the complexity of retinal arbors without affecting their laminar distribution. Thus, cell surface molecules and soluble trophic factors may collaborate to shape lamina-specific arbors in the brain, with the former predominantly affecting their position and the latter their size.
ESTHER : Inoue_1997_Science_276_1428
PubMedSearch : Inoue_1997_Science_276_1428
PubMedID: 9162013

Title : The rationale for E2020 as a potent acetylcholinesterase inhibitor - Kawakami_1996_Bioorg.Med.Chem_4_1429
Author(s) : Kawakami Y , Inoue A , Kawai T , Wakita M , Sugimoto H , Hopfinger AJ
Ref : Bioorganic & Medicinal Chemistry , 4 :1429 , 1996
Abstract : The phase III drug-candidate, E2020, developed for treatment of Alzheimer's disease, and possibly other demenitas, and its analogues have been the focus of extensive molecular pharmacological and structural studies. The potency and selectivity of E2020 as an inhibitor of acetylcholinesterase, AChE, in the brain is established. A combination of molecular modeling and QSAR studies have been used throughout the evolution of the AChE inhibitor program leading to the benzylpiperidine series, and, ultimately, E2020. QSAR studies have identified requirements of optimize inhibition activity as a function of substituent choice on both the indanone and benzyl rings in the E2020 class of inhibitors. A combination of X-ray crystal structure studies of E2020 isomers and the molecular shape analysis, MSA, of E2020 and its analogues has led to a postulated active conformation, and molecular shape, for these AChE inhibitors. The active molecular shape corresponds to a high degree of shape similarity between the two E2020 isomers which, in turn, is consistent with the observed high inhibition potencies of both of these compounds. Intermolecular docking studies were carried out for E2020 and some analogues with the crystal structure of AChE when it became available. The docking simulations involving E2020 analogues suggest these inhibitors do not bind at the acetylcholine, ACh, active site, but rather at the most narrow location of the long channel leading to the active site. Intermolecular binding geometries are consistent with the postulated active conformations derived from structure-activity (receptor geometry independent) information.
ESTHER : Kawakami_1996_Bioorg.Med.Chem_4_1429
PubMedSearch : Kawakami_1996_Bioorg.Med.Chem_4_1429
PubMedID: 8894101

Title : The simulated binding of (+\/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]m eth yl] -1H-inden-1-one hydrochloride (E2020) and related inhibitors to free and acylated acetylcholinesterases and corresponding structure-activity analyses - Inoue_1996_J.Med.Chem_39_4460
Author(s) : Inoue A , Kawai T , Wakita M , Iimura Y , Sugimoto H , Kawakami Y
Ref : Journal of Medicinal Chemistry , 39 :4460 , 1996
Abstract : The simulated binding profiles of acetylcholine, ACh, and the inhibitor (+/-)-2,3-dihydro-5,6- dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-on e hydrochloride (E2020), 1, and some of its analogs to acetylcholinesterase, AChE, were determined using full force field energetics and allowing complete conformational flexibility in both the ligand and receptor. A new mode of binding of ACh to AChE was found which involves the carboxyl oxygen of ACh interacting with Gly 118 and 119. Multiple modes of binding of 1 and some of its analogs were found which include alignment models observed in previous more restricted modeling studies. The key ligand-receptor interactions identified, and the corresponding energetics, are consistent on a relative basis, with observed binding constants for both the individual isomers of each of the inhibitors, as well as among the inhibitors themselves. The multiple modes of binding of 1 to AChE arises from small changes in binding at a single subsite and also from multiple subsite changes. Thus, an independent subsite model for ligand-receptor binding holds for some modes of binding, but not for others. A comparison of the simulated AChE-1 (and analog inhibitors) binding models to the receptor-independent 3D-QSARs previously developed for this class of inhibitors reveals extensive mutual consistency. The findings from these two modeling studies provides greater guidelines for inhibitor design than can be realized from either one. The combined docking and 3D-QSAR studies permit a detailed understanding of the SAR of more than 100 compound 1 analog inhibitors. A simple molecular recognition model can also be gleaned from the docking studies. A cylindrical "plug" (the inhibitor) having a large dipole moment must sterically fit into a cylindrical hole (the active site gorge of AChE), the lining of which also has a large dipole moment. Our simulations suggest that the dynamic "back door" to the active site of AChE does not form a large enough opening for sufficiently long time periods so as to be an effective entrance/exit pathway.
ESTHER : Inoue_1996_J.Med.Chem_39_4460
PubMedSearch : Inoue_1996_J.Med.Chem_39_4460
PubMedID: 8893840