Atp8a1 deficiency is associated with phosphatidylserine externalization in hippocampus and delayed hippocampus-dependent learning

J. Neurochem. (2012) 120, 302–313. The molecule responsible for the enzyme activity plasma membrane (PM) aminophospholipid translocase (APLT), which catalyzes phosphatidylserine (PS) translocation from the outer to the inner leaflet of the plasma membrane, is unknown in mammals. A Caenorhabditis ele...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of neurochemistry 2012-01, Vol.120 (2), p.302-313
Hauptverfasser: Levano, Kelly, Punia, Vineet, Raghunath, Michael, Debata, Priya Ranjan, Curcio, Gina Marie, Mogha, Amit, Purkayastha, Sudarshana, McCloskey, Dan, Fata, Jimmie, Banerjee, Probal
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 313
container_issue 2
container_start_page 302
container_title Journal of neurochemistry
container_volume 120
creator Levano, Kelly
Punia, Vineet
Raghunath, Michael
Debata, Priya Ranjan
Curcio, Gina Marie
Mogha, Amit
Purkayastha, Sudarshana
McCloskey, Dan
Fata, Jimmie
Banerjee, Probal
description J. Neurochem. (2012) 120, 302–313. The molecule responsible for the enzyme activity plasma membrane (PM) aminophospholipid translocase (APLT), which catalyzes phosphatidylserine (PS) translocation from the outer to the inner leaflet of the plasma membrane, is unknown in mammals. A Caenorhabditis elegans study has shown that ablation of transbilayer amphipath transporter‐1 (TAT‐1), which is an ortholog of a mammalian P‐type ATPase, Atp8a1, causes PS externalization in the germ cells. We demonstrate here that the hippocampal cells of the dentate gyrus, and Cornu Ammonis (CA1, CA3) in mice lacking Atp8a1 exhibit a dramatic increase in PS externalization. Although their hippocampi showed no abnormal morphology or heightened apoptosis, these mice displayed increased activity and a marked deficiency in hippocampus‐dependent learning, but no hyper‐anxiety. Such observations indicate that Atp8a1 plays a crucial role in PM‐APLT activity in the neuronal cells. In corroboration, ectopic expression of Atp8a1 but not its close homolog, Atp8a2, caused an increase in the population (Vmax) of PM‐APLT without any change in its signature parameter Km in the neuronal N18 cells. Conversely, expression of a P‐type phosphorylation‐site mutant of Atp8a1 (Atp8a1*) caused a decrease in Vmax of PM‐APLT without significantly altering its Km. The Atp8a1*‐expressing N18 cells also exhibited PS externalization without apoptosis. Together, our data strongly indicate that Atp8a1 plays a central role in the PM‐APLT activity of some mammalian cells, such as the neuronal N18 and hippocampal cells. A decade‐long search for the enzyme (termed ‘PM‐APLT’) that moves the lipid molecule phosphatidylserine (PS) from the outer to the inner face of the cell membrane has yielded the energy‐producing protein Atp8a1. Atp8a1 deficiency is associated with PS exposure in nerve cells and functional impairment in the nerve‐filled brain region hippocampus. Atp8a1 is most likely the PM‐APLT of nerve cells.
doi_str_mv 10.1111/j.1471-4159.2011.07543.x
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3243772</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>920791518</sourcerecordid><originalsourceid>FETCH-LOGICAL-c6003-b98d40219b59de4c9c316f0cae2202f9debe56a364bf764dbe07d6765537d3473</originalsourceid><addsrcrecordid>eNqNkk2P0zAQhiMEYsvCX0AREuKU4m_HB5BWBRbQUi4guFmOPdm6pE42TtmGG_8ch5aycAFfbM0876sZz2RZjtEcp_N0PcdM4oJhruYEYTxHkjM6393KZsfE7WyGECEFRYycZPdiXCOEBRP4bnZCCEKy5GqWfT8butLg3EHtrYdgx9zH3MTYWm8GcPm1H1Z5t2pjtzKDd2MTofcBctgN0AfT-G8p3Ibch3zlu661ZtNtk0NwybMxY7K4ES8cdBAchCFvwPTBh8v72Z3aJNcHh_s0-_jq5YfF6-Li_fmbxdlFYQVCtKhU6RgiWFVcOWBWWYpFjayB1AypU6wCLgwVrKqlYK4CJJ2QgnMqHWWSnmbP977dttqAs6mG3jS66_3G9KNujdd_ZoJf6cv2q6aEUSlJMnhyMOjbqy3EQW98tNA0JkC7jVoRJBXmuPw3iUsuJVdTUY_-ItftdvrWCcKSYIpVgso9ZPs2xh7qY9EY6Wkf9FpPY9fT2PW0D_rnPuhdkj682fRR-GsBEvD4AJhoTVP3Jlgff3Occ4kkTtyzPXftGxj_uwD9drmYXklf7PU-DrA76k3_RQtJJdeflucaLcXi8wtF9Tv6A2o04zg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>911721319</pqid></control><display><type>article</type><title>Atp8a1 deficiency is associated with phosphatidylserine externalization in hippocampus and delayed hippocampus-dependent learning</title><source>MEDLINE</source><source>Wiley Online Library Free Content</source><source>Access via Wiley Online Library</source><source>IngentaConnect Free/Open Access Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Free Full-Text Journals in Chemistry</source><creator>Levano, Kelly ; Punia, Vineet ; Raghunath, Michael ; Debata, Priya Ranjan ; Curcio, Gina Marie ; Mogha, Amit ; Purkayastha, Sudarshana ; McCloskey, Dan ; Fata, Jimmie ; Banerjee, Probal</creator><creatorcontrib>Levano, Kelly ; Punia, Vineet ; Raghunath, Michael ; Debata, Priya Ranjan ; Curcio, Gina Marie ; Mogha, Amit ; Purkayastha, Sudarshana ; McCloskey, Dan ; Fata, Jimmie ; Banerjee, Probal</creatorcontrib><description>J. Neurochem. (2012) 120, 302–313. The molecule responsible for the enzyme activity plasma membrane (PM) aminophospholipid translocase (APLT), which catalyzes phosphatidylserine (PS) translocation from the outer to the inner leaflet of the plasma membrane, is unknown in mammals. A Caenorhabditis elegans study has shown that ablation of transbilayer amphipath transporter‐1 (TAT‐1), which is an ortholog of a mammalian P‐type ATPase, Atp8a1, causes PS externalization in the germ cells. We demonstrate here that the hippocampal cells of the dentate gyrus, and Cornu Ammonis (CA1, CA3) in mice lacking Atp8a1 exhibit a dramatic increase in PS externalization. Although their hippocampi showed no abnormal morphology or heightened apoptosis, these mice displayed increased activity and a marked deficiency in hippocampus‐dependent learning, but no hyper‐anxiety. Such observations indicate that Atp8a1 plays a crucial role in PM‐APLT activity in the neuronal cells. In corroboration, ectopic expression of Atp8a1 but not its close homolog, Atp8a2, caused an increase in the population (Vmax) of PM‐APLT without any change in its signature parameter Km in the neuronal N18 cells. Conversely, expression of a P‐type phosphorylation‐site mutant of Atp8a1 (Atp8a1*) caused a decrease in Vmax of PM‐APLT without significantly altering its Km. The Atp8a1*‐expressing N18 cells also exhibited PS externalization without apoptosis. Together, our data strongly indicate that Atp8a1 plays a central role in the PM‐APLT activity of some mammalian cells, such as the neuronal N18 and hippocampal cells. A decade‐long search for the enzyme (termed ‘PM‐APLT’) that moves the lipid molecule phosphatidylserine (PS) from the outer to the inner face of the cell membrane has yielded the energy‐producing protein Atp8a1. Atp8a1 deficiency is associated with PS exposure in nerve cells and functional impairment in the nerve‐filled brain region hippocampus. Atp8a1 is most likely the PM‐APLT of nerve cells.</description><identifier>ISSN: 0022-3042</identifier><identifier>EISSN: 1471-4159</identifier><identifier>DOI: 10.1111/j.1471-4159.2011.07543.x</identifier><identifier>PMID: 22007859</identifier><identifier>CODEN: JONRA9</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Adenosine Triphosphatases - deficiency ; Adenosinetriphosphatase ; aminophospholipid translocase ; Animals ; Annexin A5 - metabolism ; Apoptosis ; Atp8a1 ; Biological and medical sciences ; Brain ; Brain research ; Caenorhabditis elegans ; Cell Membrane - metabolism ; Cell membranes ; Central nervous system ; Central neurotransmission. Neuromudulation. Pathways and receptors ; Data processing ; Dentate gyrus ; Electrophysiology ; Enzymes ; Female ; Fundamental and applied biological sciences. Psychology ; Gene Expression Regulation - genetics ; Germ cells ; Hippocampus ; Hippocampus - metabolism ; Hippocampus - physiology ; Learning ; Lipids ; Male ; Mammalian cells ; Maze Learning - physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation - genetics ; Nerves ; Neurochemistry ; Organ Culture Techniques ; phosphatidylserine ; Phosphatidylserines - metabolism ; Phospholipid Transfer Proteins - deficiency ; Phospholipid Transfer Proteins - metabolism ; Phosphorylation ; Phosphorylation - genetics ; Plasma ; Plasma membranes ; Protein Transport - genetics ; spatial memory ; translocase ; Translocation ; Vertebrates: nervous system and sense organs</subject><ispartof>Journal of neurochemistry, 2012-01, Vol.120 (2), p.302-313</ispartof><rights>2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry</rights><rights>2015 INIST-CNRS</rights><rights>2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6003-b98d40219b59de4c9c316f0cae2202f9debe56a364bf764dbe07d6765537d3473</citedby><cites>FETCH-LOGICAL-c6003-b98d40219b59de4c9c316f0cae2202f9debe56a364bf764dbe07d6765537d3473</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1471-4159.2011.07543.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1471-4159.2011.07543.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=25557071$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22007859$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Levano, Kelly</creatorcontrib><creatorcontrib>Punia, Vineet</creatorcontrib><creatorcontrib>Raghunath, Michael</creatorcontrib><creatorcontrib>Debata, Priya Ranjan</creatorcontrib><creatorcontrib>Curcio, Gina Marie</creatorcontrib><creatorcontrib>Mogha, Amit</creatorcontrib><creatorcontrib>Purkayastha, Sudarshana</creatorcontrib><creatorcontrib>McCloskey, Dan</creatorcontrib><creatorcontrib>Fata, Jimmie</creatorcontrib><creatorcontrib>Banerjee, Probal</creatorcontrib><title>Atp8a1 deficiency is associated with phosphatidylserine externalization in hippocampus and delayed hippocampus-dependent learning</title><title>Journal of neurochemistry</title><addtitle>J Neurochem</addtitle><description>J. Neurochem. (2012) 120, 302–313. The molecule responsible for the enzyme activity plasma membrane (PM) aminophospholipid translocase (APLT), which catalyzes phosphatidylserine (PS) translocation from the outer to the inner leaflet of the plasma membrane, is unknown in mammals. A Caenorhabditis elegans study has shown that ablation of transbilayer amphipath transporter‐1 (TAT‐1), which is an ortholog of a mammalian P‐type ATPase, Atp8a1, causes PS externalization in the germ cells. We demonstrate here that the hippocampal cells of the dentate gyrus, and Cornu Ammonis (CA1, CA3) in mice lacking Atp8a1 exhibit a dramatic increase in PS externalization. Although their hippocampi showed no abnormal morphology or heightened apoptosis, these mice displayed increased activity and a marked deficiency in hippocampus‐dependent learning, but no hyper‐anxiety. Such observations indicate that Atp8a1 plays a crucial role in PM‐APLT activity in the neuronal cells. In corroboration, ectopic expression of Atp8a1 but not its close homolog, Atp8a2, caused an increase in the population (Vmax) of PM‐APLT without any change in its signature parameter Km in the neuronal N18 cells. Conversely, expression of a P‐type phosphorylation‐site mutant of Atp8a1 (Atp8a1*) caused a decrease in Vmax of PM‐APLT without significantly altering its Km. The Atp8a1*‐expressing N18 cells also exhibited PS externalization without apoptosis. Together, our data strongly indicate that Atp8a1 plays a central role in the PM‐APLT activity of some mammalian cells, such as the neuronal N18 and hippocampal cells. A decade‐long search for the enzyme (termed ‘PM‐APLT’) that moves the lipid molecule phosphatidylserine (PS) from the outer to the inner face of the cell membrane has yielded the energy‐producing protein Atp8a1. Atp8a1 deficiency is associated with PS exposure in nerve cells and functional impairment in the nerve‐filled brain region hippocampus. Atp8a1 is most likely the PM‐APLT of nerve cells.</description><subject>Adenosine Triphosphatases - deficiency</subject><subject>Adenosinetriphosphatase</subject><subject>aminophospholipid translocase</subject><subject>Animals</subject><subject>Annexin A5 - metabolism</subject><subject>Apoptosis</subject><subject>Atp8a1</subject><subject>Biological and medical sciences</subject><subject>Brain</subject><subject>Brain research</subject><subject>Caenorhabditis elegans</subject><subject>Cell Membrane - metabolism</subject><subject>Cell membranes</subject><subject>Central nervous system</subject><subject>Central neurotransmission. Neuromudulation. Pathways and receptors</subject><subject>Data processing</subject><subject>Dentate gyrus</subject><subject>Electrophysiology</subject><subject>Enzymes</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Expression Regulation - genetics</subject><subject>Germ cells</subject><subject>Hippocampus</subject><subject>Hippocampus - metabolism</subject><subject>Hippocampus - physiology</subject><subject>Learning</subject><subject>Lipids</subject><subject>Male</subject><subject>Mammalian cells</subject><subject>Maze Learning - physiology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mutation - genetics</subject><subject>Nerves</subject><subject>Neurochemistry</subject><subject>Organ Culture Techniques</subject><subject>phosphatidylserine</subject><subject>Phosphatidylserines - metabolism</subject><subject>Phospholipid Transfer Proteins - deficiency</subject><subject>Phospholipid Transfer Proteins - metabolism</subject><subject>Phosphorylation</subject><subject>Phosphorylation - genetics</subject><subject>Plasma</subject><subject>Plasma membranes</subject><subject>Protein Transport - genetics</subject><subject>spatial memory</subject><subject>translocase</subject><subject>Translocation</subject><subject>Vertebrates: nervous system and sense organs</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkk2P0zAQhiMEYsvCX0AREuKU4m_HB5BWBRbQUi4guFmOPdm6pE42TtmGG_8ch5aycAFfbM0876sZz2RZjtEcp_N0PcdM4oJhruYEYTxHkjM6393KZsfE7WyGECEFRYycZPdiXCOEBRP4bnZCCEKy5GqWfT8butLg3EHtrYdgx9zH3MTYWm8GcPm1H1Z5t2pjtzKDd2MTofcBctgN0AfT-G8p3Ibch3zlu661ZtNtk0NwybMxY7K4ES8cdBAchCFvwPTBh8v72Z3aJNcHh_s0-_jq5YfF6-Li_fmbxdlFYQVCtKhU6RgiWFVcOWBWWYpFjayB1AypU6wCLgwVrKqlYK4CJJ2QgnMqHWWSnmbP977dttqAs6mG3jS66_3G9KNujdd_ZoJf6cv2q6aEUSlJMnhyMOjbqy3EQW98tNA0JkC7jVoRJBXmuPw3iUsuJVdTUY_-ItftdvrWCcKSYIpVgso9ZPs2xh7qY9EY6Wkf9FpPY9fT2PW0D_rnPuhdkj682fRR-GsBEvD4AJhoTVP3Jlgff3Occ4kkTtyzPXftGxj_uwD9drmYXklf7PU-DrA76k3_RQtJJdeflucaLcXi8wtF9Tv6A2o04zg</recordid><startdate>201201</startdate><enddate>201201</enddate><creator>Levano, Kelly</creator><creator>Punia, Vineet</creator><creator>Raghunath, Michael</creator><creator>Debata, Priya Ranjan</creator><creator>Curcio, Gina Marie</creator><creator>Mogha, Amit</creator><creator>Purkayastha, Sudarshana</creator><creator>McCloskey, Dan</creator><creator>Fata, Jimmie</creator><creator>Banerjee, Probal</creator><general>Blackwell Publishing Ltd</general><general>Wiley-Blackwell</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201201</creationdate><title>Atp8a1 deficiency is associated with phosphatidylserine externalization in hippocampus and delayed hippocampus-dependent learning</title><author>Levano, Kelly ; Punia, Vineet ; Raghunath, Michael ; Debata, Priya Ranjan ; Curcio, Gina Marie ; Mogha, Amit ; Purkayastha, Sudarshana ; McCloskey, Dan ; Fata, Jimmie ; Banerjee, Probal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6003-b98d40219b59de4c9c316f0cae2202f9debe56a364bf764dbe07d6765537d3473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adenosine Triphosphatases - deficiency</topic><topic>Adenosinetriphosphatase</topic><topic>aminophospholipid translocase</topic><topic>Animals</topic><topic>Annexin A5 - metabolism</topic><topic>Apoptosis</topic><topic>Atp8a1</topic><topic>Biological and medical sciences</topic><topic>Brain</topic><topic>Brain research</topic><topic>Caenorhabditis elegans</topic><topic>Cell Membrane - metabolism</topic><topic>Cell membranes</topic><topic>Central nervous system</topic><topic>Central neurotransmission. Neuromudulation. Pathways and receptors</topic><topic>Data processing</topic><topic>Dentate gyrus</topic><topic>Electrophysiology</topic><topic>Enzymes</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene Expression Regulation - genetics</topic><topic>Germ cells</topic><topic>Hippocampus</topic><topic>Hippocampus - metabolism</topic><topic>Hippocampus - physiology</topic><topic>Learning</topic><topic>Lipids</topic><topic>Male</topic><topic>Mammalian cells</topic><topic>Maze Learning - physiology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mutation - genetics</topic><topic>Nerves</topic><topic>Neurochemistry</topic><topic>Organ Culture Techniques</topic><topic>phosphatidylserine</topic><topic>Phosphatidylserines - metabolism</topic><topic>Phospholipid Transfer Proteins - deficiency</topic><topic>Phospholipid Transfer Proteins - metabolism</topic><topic>Phosphorylation</topic><topic>Phosphorylation - genetics</topic><topic>Plasma</topic><topic>Plasma membranes</topic><topic>Protein Transport - genetics</topic><topic>spatial memory</topic><topic>translocase</topic><topic>Translocation</topic><topic>Vertebrates: nervous system and sense organs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Levano, Kelly</creatorcontrib><creatorcontrib>Punia, Vineet</creatorcontrib><creatorcontrib>Raghunath, Michael</creatorcontrib><creatorcontrib>Debata, Priya Ranjan</creatorcontrib><creatorcontrib>Curcio, Gina Marie</creatorcontrib><creatorcontrib>Mogha, Amit</creatorcontrib><creatorcontrib>Purkayastha, Sudarshana</creatorcontrib><creatorcontrib>McCloskey, Dan</creatorcontrib><creatorcontrib>Fata, Jimmie</creatorcontrib><creatorcontrib>Banerjee, Probal</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Levano, Kelly</au><au>Punia, Vineet</au><au>Raghunath, Michael</au><au>Debata, Priya Ranjan</au><au>Curcio, Gina Marie</au><au>Mogha, Amit</au><au>Purkayastha, Sudarshana</au><au>McCloskey, Dan</au><au>Fata, Jimmie</au><au>Banerjee, Probal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Atp8a1 deficiency is associated with phosphatidylserine externalization in hippocampus and delayed hippocampus-dependent learning</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>2012-01</date><risdate>2012</risdate><volume>120</volume><issue>2</issue><spage>302</spage><epage>313</epage><pages>302-313</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><coden>JONRA9</coden><abstract>J. Neurochem. (2012) 120, 302–313. The molecule responsible for the enzyme activity plasma membrane (PM) aminophospholipid translocase (APLT), which catalyzes phosphatidylserine (PS) translocation from the outer to the inner leaflet of the plasma membrane, is unknown in mammals. A Caenorhabditis elegans study has shown that ablation of transbilayer amphipath transporter‐1 (TAT‐1), which is an ortholog of a mammalian P‐type ATPase, Atp8a1, causes PS externalization in the germ cells. We demonstrate here that the hippocampal cells of the dentate gyrus, and Cornu Ammonis (CA1, CA3) in mice lacking Atp8a1 exhibit a dramatic increase in PS externalization. Although their hippocampi showed no abnormal morphology or heightened apoptosis, these mice displayed increased activity and a marked deficiency in hippocampus‐dependent learning, but no hyper‐anxiety. Such observations indicate that Atp8a1 plays a crucial role in PM‐APLT activity in the neuronal cells. In corroboration, ectopic expression of Atp8a1 but not its close homolog, Atp8a2, caused an increase in the population (Vmax) of PM‐APLT without any change in its signature parameter Km in the neuronal N18 cells. Conversely, expression of a P‐type phosphorylation‐site mutant of Atp8a1 (Atp8a1*) caused a decrease in Vmax of PM‐APLT without significantly altering its Km. The Atp8a1*‐expressing N18 cells also exhibited PS externalization without apoptosis. Together, our data strongly indicate that Atp8a1 plays a central role in the PM‐APLT activity of some mammalian cells, such as the neuronal N18 and hippocampal cells. A decade‐long search for the enzyme (termed ‘PM‐APLT’) that moves the lipid molecule phosphatidylserine (PS) from the outer to the inner face of the cell membrane has yielded the energy‐producing protein Atp8a1. Atp8a1 deficiency is associated with PS exposure in nerve cells and functional impairment in the nerve‐filled brain region hippocampus. Atp8a1 is most likely the PM‐APLT of nerve cells.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>22007859</pmid><doi>10.1111/j.1471-4159.2011.07543.x</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0022-3042
ispartof Journal of neurochemistry, 2012-01, Vol.120 (2), p.302-313
issn 0022-3042
1471-4159
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3243772
source MEDLINE; Wiley Online Library Free Content; Access via Wiley Online Library; IngentaConnect Free/Open Access Journals; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry
subjects Adenosine Triphosphatases - deficiency
Adenosinetriphosphatase
aminophospholipid translocase
Animals
Annexin A5 - metabolism
Apoptosis
Atp8a1
Biological and medical sciences
Brain
Brain research
Caenorhabditis elegans
Cell Membrane - metabolism
Cell membranes
Central nervous system
Central neurotransmission. Neuromudulation. Pathways and receptors
Data processing
Dentate gyrus
Electrophysiology
Enzymes
Female
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation - genetics
Germ cells
Hippocampus
Hippocampus - metabolism
Hippocampus - physiology
Learning
Lipids
Male
Mammalian cells
Maze Learning - physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation - genetics
Nerves
Neurochemistry
Organ Culture Techniques
phosphatidylserine
Phosphatidylserines - metabolism
Phospholipid Transfer Proteins - deficiency
Phospholipid Transfer Proteins - metabolism
Phosphorylation
Phosphorylation - genetics
Plasma
Plasma membranes
Protein Transport - genetics
spatial memory
translocase
Translocation
Vertebrates: nervous system and sense organs
title Atp8a1 deficiency is associated with phosphatidylserine externalization in hippocampus and delayed hippocampus-dependent learning
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T00%3A36%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Atp8a1%20deficiency%20is%20associated%20with%20phosphatidylserine%20externalization%20in%20hippocampus%20and%20delayed%20hippocampus-dependent%20learning&rft.jtitle=Journal%20of%20neurochemistry&rft.au=Levano,%20Kelly&rft.date=2012-01&rft.volume=120&rft.issue=2&rft.spage=302&rft.epage=313&rft.pages=302-313&rft.issn=0022-3042&rft.eissn=1471-4159&rft.coden=JONRA9&rft_id=info:doi/10.1111/j.1471-4159.2011.07543.x&rft_dat=%3Cproquest_pubme%3E920791518%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=911721319&rft_id=info:pmid/22007859&rfr_iscdi=true