Crucial role of copper in detection of metal-coordinating odorants
Odorant receptors (ORs) in olfactory sensory neurons (OSNs) mediate detection of volatile odorants. Divalent sulfur compounds, such as thiols and thioethers, are extremely potent odorants. We identify a mouse OR, MOR244-3, robustly responding to (methylthio)methanethiol (MeSCH2SH; MTMT) in heterolog...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2012-02, Vol.109 (9), p.3492-3497 |
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| creator | Duan, Xufang Block, Eric Li, Zhen Connelly, Timothy Zhang, Jian Huang, Zhimin Su, Xubo Pan, Yi Wu, Lifang Chi, Qiuyi Thomas, Siji Zhang, Shaozhong Ma, Minghong Matsunami, Hiroaki Chen, Guo-Qiang Zhuang, Hanyi |
| description | Odorant receptors (ORs) in olfactory sensory neurons (OSNs) mediate detection of volatile odorants. Divalent sulfur compounds, such as thiols and thioethers, are extremely potent odorants. We identify a mouse OR, MOR244-3, robustly responding to (methylthio)methanethiol (MeSCH2SH; MTMT) in heterologous cells. Found specifically in male mouse urine, strong-smelling MTMT [human threshold 100 parts per billion (ppb)] is a semiochemical that attracts female mice. Nonadjacent thiol and thioether groups in MTMT suggest involvement of a chelated metal complex in MOR244-3 activation. Metal ion involvement in thiol–OR interactions was previously proposed, but whether these ions change thiol-mediated OR activation remained unknown. We show that copper ion among all metal ions tested is required for robust activation of MOR244-3 toward ppb levels of MTMT, structurally related sulfur compounds, and other metal-coordinating odorants (e.g., strong-smelling trans-cyclooctene) among >125 compounds tested. Copper chelator (tetraethylenepentamine, TEPA) addition abolishes the response of MOR244-3 to MTMT. Histidine 105, located in the third transmembrane domain near the extracellular side, is proposed to serve as a copper-coordinating residue mediating interaction with the MTMT–copper complex. Electrophysiological recordings of the OSNs in the septal organ, abundantly expressing MOR244-3, revealed neurons responding to MTMT. Addition of copper ion and chelator TEPA respectively enhanced and reduced the response of some MTMT-responding neurons, demonstrating the physiological relevance of copper ion in olfaction. In a behavioral context, an olfactory discrimination assay showed that mice injected with TEPA failed to discriminate MTMT. This report establishes the role of metal ions in mammalian odor detection by ORs. |
| doi_str_mv | 10.1073/pnas.1111297109 |
| format | Article |
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Divalent sulfur compounds, such as thiols and thioethers, are extremely potent odorants. We identify a mouse OR, MOR244-3, robustly responding to (methylthio)methanethiol (MeSCH2SH; MTMT) in heterologous cells. Found specifically in male mouse urine, strong-smelling MTMT [human threshold 100 parts per billion (ppb)] is a semiochemical that attracts female mice. Nonadjacent thiol and thioether groups in MTMT suggest involvement of a chelated metal complex in MOR244-3 activation. Metal ion involvement in thiol–OR interactions was previously proposed, but whether these ions change thiol-mediated OR activation remained unknown. We show that copper ion among all metal ions tested is required for robust activation of MOR244-3 toward ppb levels of MTMT, structurally related sulfur compounds, and other metal-coordinating odorants (e.g., strong-smelling trans-cyclooctene) among >125 compounds tested. Copper chelator (tetraethylenepentamine, TEPA) addition abolishes the response of MOR244-3 to MTMT. Histidine 105, located in the third transmembrane domain near the extracellular side, is proposed to serve as a copper-coordinating residue mediating interaction with the MTMT–copper complex. Electrophysiological recordings of the OSNs in the septal organ, abundantly expressing MOR244-3, revealed neurons responding to MTMT. Addition of copper ion and chelator TEPA respectively enhanced and reduced the response of some MTMT-responding neurons, demonstrating the physiological relevance of copper ion in olfaction. In a behavioral context, an olfactory discrimination assay showed that mice injected with TEPA failed to discriminate MTMT. This report establishes the role of metal ions in mammalian odor detection by ORs.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1111297109</identifier><identifier>PMID: 22328155</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Amino Acid Sequence ; Animals ; Biological Sciences ; Cadmium ; Cations - pharmacology ; Cells ; Chelating agents ; Chelating Agents - pharmacology ; Copper ; Copper - physiology ; Cyclic AMP - analysis ; Disulfides ; Dose-Response Relationship, Drug ; Electrophysiological recording ; Ethylenediamines - pharmacology ; Female ; Heavy metals ; Histidine ; Histidine - chemistry ; Humans ; Ions ; Ligands ; Male ; Metal ions ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Molecular Sequence Data ; Neurons ; odor compounds ; Odorant receptors ; Odorants ; Odors ; Olfaction ; Olfactory discrimination ; Olfactory perception ; Olfactory receptor neurons ; Olfactory Receptor Neurons - metabolism ; Patch-Clamp Techniques ; Physical Sciences ; Protein Conformation ; Protein Structure, Tertiary ; Receptors ; Receptors, Odorant - chemistry ; Receptors, Odorant - genetics ; Receptors, Odorant - physiology ; Rodents ; Semiochemicals ; Sensory neurons ; Sequence Alignment ; Sequence Homology, Amino Acid ; Sex Attractants - metabolism ; smell ; Structure-Activity Relationship ; Substrate Specificity ; Sulfhydryl Compounds - metabolism ; Sulfides ; Sulfides - metabolism ; sulfur ; sulfur compounds ; Sulfur Compounds - metabolism ; thioethers ; Thiols ; Transmembrane domains ; urine ; Volatiles</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2012-02, Vol.109 (9), p.3492-3497</ispartof><rights>copyright © 1993-2008 National Acadamy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Feb 28, 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c620t-1a54fae5e7a3dbc3008acb523c8efa835e43c03aa3a930384f675d63fcdb696d3</citedby><cites>FETCH-LOGICAL-c620t-1a54fae5e7a3dbc3008acb523c8efa835e43c03aa3a930384f675d63fcdb696d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/109/9.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/41506978$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/41506978$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22328155$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Duan, Xufang</creatorcontrib><creatorcontrib>Block, Eric</creatorcontrib><creatorcontrib>Li, Zhen</creatorcontrib><creatorcontrib>Connelly, Timothy</creatorcontrib><creatorcontrib>Zhang, Jian</creatorcontrib><creatorcontrib>Huang, Zhimin</creatorcontrib><creatorcontrib>Su, Xubo</creatorcontrib><creatorcontrib>Pan, Yi</creatorcontrib><creatorcontrib>Wu, Lifang</creatorcontrib><creatorcontrib>Chi, Qiuyi</creatorcontrib><creatorcontrib>Thomas, Siji</creatorcontrib><creatorcontrib>Zhang, Shaozhong</creatorcontrib><creatorcontrib>Ma, Minghong</creatorcontrib><creatorcontrib>Matsunami, Hiroaki</creatorcontrib><creatorcontrib>Chen, Guo-Qiang</creatorcontrib><creatorcontrib>Zhuang, Hanyi</creatorcontrib><title>Crucial role of copper in detection of metal-coordinating odorants</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Odorant receptors (ORs) in olfactory sensory neurons (OSNs) mediate detection of volatile odorants. Divalent sulfur compounds, such as thiols and thioethers, are extremely potent odorants. We identify a mouse OR, MOR244-3, robustly responding to (methylthio)methanethiol (MeSCH2SH; MTMT) in heterologous cells. Found specifically in male mouse urine, strong-smelling MTMT [human threshold 100 parts per billion (ppb)] is a semiochemical that attracts female mice. Nonadjacent thiol and thioether groups in MTMT suggest involvement of a chelated metal complex in MOR244-3 activation. Metal ion involvement in thiol–OR interactions was previously proposed, but whether these ions change thiol-mediated OR activation remained unknown. We show that copper ion among all metal ions tested is required for robust activation of MOR244-3 toward ppb levels of MTMT, structurally related sulfur compounds, and other metal-coordinating odorants (e.g., strong-smelling trans-cyclooctene) among >125 compounds tested. Copper chelator (tetraethylenepentamine, TEPA) addition abolishes the response of MOR244-3 to MTMT. Histidine 105, located in the third transmembrane domain near the extracellular side, is proposed to serve as a copper-coordinating residue mediating interaction with the MTMT–copper complex. Electrophysiological recordings of the OSNs in the septal organ, abundantly expressing MOR244-3, revealed neurons responding to MTMT. Addition of copper ion and chelator TEPA respectively enhanced and reduced the response of some MTMT-responding neurons, demonstrating the physiological relevance of copper ion in olfaction. In a behavioral context, an olfactory discrimination assay showed that mice injected with TEPA failed to discriminate MTMT. This report establishes the role of metal ions in mammalian odor detection by ORs.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Cadmium</subject><subject>Cations - pharmacology</subject><subject>Cells</subject><subject>Chelating agents</subject><subject>Chelating Agents - pharmacology</subject><subject>Copper</subject><subject>Copper - physiology</subject><subject>Cyclic AMP - analysis</subject><subject>Disulfides</subject><subject>Dose-Response Relationship, Drug</subject><subject>Electrophysiological recording</subject><subject>Ethylenediamines - pharmacology</subject><subject>Female</subject><subject>Heavy metals</subject><subject>Histidine</subject><subject>Histidine - chemistry</subject><subject>Humans</subject><subject>Ions</subject><subject>Ligands</subject><subject>Male</subject><subject>Metal ions</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Neurons</subject><subject>odor compounds</subject><subject>Odorant receptors</subject><subject>Odorants</subject><subject>Odors</subject><subject>Olfaction</subject><subject>Olfactory discrimination</subject><subject>Olfactory perception</subject><subject>Olfactory receptor neurons</subject><subject>Olfactory Receptor Neurons - metabolism</subject><subject>Patch-Clamp Techniques</subject><subject>Physical Sciences</subject><subject>Protein Conformation</subject><subject>Protein Structure, Tertiary</subject><subject>Receptors</subject><subject>Receptors, Odorant - chemistry</subject><subject>Receptors, Odorant - genetics</subject><subject>Receptors, Odorant - physiology</subject><subject>Rodents</subject><subject>Semiochemicals</subject><subject>Sensory neurons</subject><subject>Sequence Alignment</subject><subject>Sequence Homology, Amino Acid</subject><subject>Sex Attractants - metabolism</subject><subject>smell</subject><subject>Structure-Activity Relationship</subject><subject>Substrate Specificity</subject><subject>Sulfhydryl Compounds - metabolism</subject><subject>Sulfides</subject><subject>Sulfides - metabolism</subject><subject>sulfur</subject><subject>sulfur compounds</subject><subject>Sulfur Compounds - metabolism</subject><subject>thioethers</subject><subject>Thiols</subject><subject>Transmembrane domains</subject><subject>urine</subject><subject>Volatiles</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks2PFCEQxYnRuOPq2ZPa8eSldwtovi6b6MSvZBMPumdSQ9Mjkx4YodvE_146s86uXuQACfWrl1c8CHlO4YKC4peHiOWC1sWMomAekFXdaSs7Aw_JCoCpVnesOyNPStkBgBEaHpMzxjjTVIgVebfOsws4NjmNvklD49Lh4HMTYtP7ybsppLhc7_2EY-tSyn2IOIW4bVKfMsapPCWPBhyLf3Z7npObD--_rT-1118-fl6_vW6dZDC1FEU3oBdeIe83jgNodBvBuNN-QM2F77gDjsjRcOC6G6QSveSD6zfSyJ6fk6uj7mHe7H3vfJwyjvaQwx7zL5sw2L8rMXy32_TTcmZEHbcKvLkVyOnH7Mtk96E4P44YfZqLZUZLJkEZ9V-UVvead6BZRV__g-7SnGN9CWuYFEIoYSp0eYRcTqVkP5xsU7BLknZJ0t4lWTte3p_2xP-J7h6wdN7JGWss78xi7MUR2JUp5RPRUQHSKF3rr471AZPFbQ7F3nxlQLv6TzRVNYPfGqG21w</recordid><startdate>20120228</startdate><enddate>20120228</enddate><creator>Duan, Xufang</creator><creator>Block, Eric</creator><creator>Li, Zhen</creator><creator>Connelly, Timothy</creator><creator>Zhang, Jian</creator><creator>Huang, Zhimin</creator><creator>Su, Xubo</creator><creator>Pan, Yi</creator><creator>Wu, Lifang</creator><creator>Chi, Qiuyi</creator><creator>Thomas, Siji</creator><creator>Zhang, Shaozhong</creator><creator>Ma, Minghong</creator><creator>Matsunami, Hiroaki</creator><creator>Chen, Guo-Qiang</creator><creator>Zhuang, Hanyi</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20120228</creationdate><title>Crucial role of copper in detection of metal-coordinating odorants</title><author>Duan, Xufang ; Block, Eric ; Li, Zhen ; Connelly, Timothy ; Zhang, Jian ; Huang, Zhimin ; Su, Xubo ; Pan, Yi ; Wu, Lifang ; Chi, Qiuyi ; Thomas, Siji ; Zhang, Shaozhong ; Ma, Minghong ; Matsunami, Hiroaki ; Chen, Guo-Qiang ; Zhuang, Hanyi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c620t-1a54fae5e7a3dbc3008acb523c8efa835e43c03aa3a930384f675d63fcdb696d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Biological Sciences</topic><topic>Cadmium</topic><topic>Cations - pharmacology</topic><topic>Cells</topic><topic>Chelating agents</topic><topic>Chelating Agents - pharmacology</topic><topic>Copper</topic><topic>Copper - physiology</topic><topic>Cyclic AMP - analysis</topic><topic>Disulfides</topic><topic>Dose-Response Relationship, Drug</topic><topic>Electrophysiological recording</topic><topic>Ethylenediamines - pharmacology</topic><topic>Female</topic><topic>Heavy metals</topic><topic>Histidine</topic><topic>Histidine - chemistry</topic><topic>Humans</topic><topic>Ions</topic><topic>Ligands</topic><topic>Male</topic><topic>Metal ions</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Neurons</topic><topic>odor compounds</topic><topic>Odorant receptors</topic><topic>Odorants</topic><topic>Odors</topic><topic>Olfaction</topic><topic>Olfactory discrimination</topic><topic>Olfactory perception</topic><topic>Olfactory receptor neurons</topic><topic>Olfactory Receptor Neurons - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Duan, Xufang</au><au>Block, Eric</au><au>Li, Zhen</au><au>Connelly, Timothy</au><au>Zhang, Jian</au><au>Huang, Zhimin</au><au>Su, Xubo</au><au>Pan, Yi</au><au>Wu, Lifang</au><au>Chi, Qiuyi</au><au>Thomas, Siji</au><au>Zhang, Shaozhong</au><au>Ma, Minghong</au><au>Matsunami, Hiroaki</au><au>Chen, Guo-Qiang</au><au>Zhuang, Hanyi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Crucial role of copper in detection of metal-coordinating odorants</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2012-02-28</date><risdate>2012</risdate><volume>109</volume><issue>9</issue><spage>3492</spage><epage>3497</epage><pages>3492-3497</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Odorant receptors (ORs) in olfactory sensory neurons (OSNs) mediate detection of volatile odorants. Divalent sulfur compounds, such as thiols and thioethers, are extremely potent odorants. We identify a mouse OR, MOR244-3, robustly responding to (methylthio)methanethiol (MeSCH2SH; MTMT) in heterologous cells. Found specifically in male mouse urine, strong-smelling MTMT [human threshold 100 parts per billion (ppb)] is a semiochemical that attracts female mice. Nonadjacent thiol and thioether groups in MTMT suggest involvement of a chelated metal complex in MOR244-3 activation. Metal ion involvement in thiol–OR interactions was previously proposed, but whether these ions change thiol-mediated OR activation remained unknown. We show that copper ion among all metal ions tested is required for robust activation of MOR244-3 toward ppb levels of MTMT, structurally related sulfur compounds, and other metal-coordinating odorants (e.g., strong-smelling trans-cyclooctene) among >125 compounds tested. Copper chelator (tetraethylenepentamine, TEPA) addition abolishes the response of MOR244-3 to MTMT. Histidine 105, located in the third transmembrane domain near the extracellular side, is proposed to serve as a copper-coordinating residue mediating interaction with the MTMT–copper complex. Electrophysiological recordings of the OSNs in the septal organ, abundantly expressing MOR244-3, revealed neurons responding to MTMT. Addition of copper ion and chelator TEPA respectively enhanced and reduced the response of some MTMT-responding neurons, demonstrating the physiological relevance of copper ion in olfaction. In a behavioral context, an olfactory discrimination assay showed that mice injected with TEPA failed to discriminate MTMT. This report establishes the role of metal ions in mammalian odor detection by ORs.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>22328155</pmid><doi>10.1073/pnas.1111297109</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2012-02, Vol.109 (9), p.3492-3497 |
| issn | 0027-8424 1091-6490 |
| language | eng |
| recordid | cdi_fao_agris_US201400081730 |
| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Sequence Animals Biological Sciences Cadmium Cations - pharmacology Cells Chelating agents Chelating Agents - pharmacology Copper Copper - physiology Cyclic AMP - analysis Disulfides Dose-Response Relationship, Drug Electrophysiological recording Ethylenediamines - pharmacology Female Heavy metals Histidine Histidine - chemistry Humans Ions Ligands Male Metal ions Mice Mice, Inbred C57BL Models, Molecular Molecular Sequence Data Neurons odor compounds Odorant receptors Odorants Odors Olfaction Olfactory discrimination Olfactory perception Olfactory receptor neurons Olfactory Receptor Neurons - metabolism Patch-Clamp Techniques Physical Sciences Protein Conformation Protein Structure, Tertiary Receptors Receptors, Odorant - chemistry Receptors, Odorant - genetics Receptors, Odorant - physiology Rodents Semiochemicals Sensory neurons Sequence Alignment Sequence Homology, Amino Acid Sex Attractants - metabolism smell Structure-Activity Relationship Substrate Specificity Sulfhydryl Compounds - metabolism Sulfides Sulfides - metabolism sulfur sulfur compounds Sulfur Compounds - metabolism thioethers Thiols Transmembrane domains urine Volatiles |
| title | Crucial role of copper in detection of metal-coordinating odorants |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T02%3A37%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_fao_a&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Crucial%20role%20of%20copper%20in%20detection%20of%20metal-coordinating%20odorants&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Duan,%20Xufang&rft.date=2012-02-28&rft.volume=109&rft.issue=9&rft.spage=3492&rft.epage=3497&rft.pages=3492-3497&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.1111297109&rft_dat=%3Cjstor_fao_a%3E41506978%3C/jstor_fao_a%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=926555759&rft_id=info:pmid/22328155&rft_jstor_id=41506978&rfr_iscdi=true |