Multiple pathways of thrombin-induced platelet activation differentiated by desensitization and a thrombin exosite inhibitor
Recently a thrombin receptor with a unique mechanism of activation was cloned from a megakaryocyte-like cell line (Vu et al., Cell 64 :1057–1068, 1991). Thrombin cleaves a portion of this receptor creating a new N-terminus that acts as a “tethered-ligand” to activate the receptor. A thrombin recepto...
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| Veröffentlicht in: | Biochemical and biophysical research communications 1991-12, Vol.181 (2), p.636-643 |
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| container_title | Biochemical and biophysical research communications |
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| creator | Seiler, Steven M. Goldenberg, Harold J. Michel, Inge M. Hunt, John T. Zavoico, George B. |
| description | Recently a thrombin receptor with a unique mechanism of activation was cloned from a megakaryocyte-like cell line (Vu et al., Cell
64
:1057–1068, 1991). Thrombin cleaves a portion of this receptor creating a new N-terminus that acts as a “tethered-ligand” to activate the receptor. A thrombin receptor activating peptide (SFLLRNPNDKYEPF) homologous to the new N-terminus was shown to activate platelets. We synthesized this peptide and demonstrated that it desensitized platelets to activation by low concentrations of α-thrombin but not γ-thrombin. We also synthesized a thrombin exosite inhibitor (BMS 180742) that inhibited platelet aggregation induced by low, but not high, concentrations of α-thrombin. In contrast, a thrombin active site inhibitor, Nα-(2-naphthylsulfonyl-glycyl)-D,L-amidinophenylalanylpiperidide, competitively inhibited thrombin-induced platelet aggregation. We conclude that thrombin-induced platelet activation is mediated by at least two pathways: one activated by low concentrations of α-thrombin and blocked by a thrombin exosite inhibitor that appears to be coupled to the “tethered-ligand” thrombin receptor, and another that is stimulated by higher concentrations of α-thrombin and by γ-thrombin and does not require the thrombin exosite for activation. Both pathways are blocked by a thrombin active site inhibitor. |
| doi_str_mv | 10.1016/0006-291X(91)91238-8 |
| format | Article |
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:1057–1068, 1991). Thrombin cleaves a portion of this receptor creating a new N-terminus that acts as a “tethered-ligand” to activate the receptor. A thrombin receptor activating peptide (SFLLRNPNDKYEPF) homologous to the new N-terminus was shown to activate platelets. We synthesized this peptide and demonstrated that it desensitized platelets to activation by low concentrations of α-thrombin but not γ-thrombin. We also synthesized a thrombin exosite inhibitor (BMS 180742) that inhibited platelet aggregation induced by low, but not high, concentrations of α-thrombin. In contrast, a thrombin active site inhibitor, Nα-(2-naphthylsulfonyl-glycyl)-D,L-amidinophenylalanylpiperidide, competitively inhibited thrombin-induced platelet aggregation. We conclude that thrombin-induced platelet activation is mediated by at least two pathways: one activated by low concentrations of α-thrombin and blocked by a thrombin exosite inhibitor that appears to be coupled to the “tethered-ligand” thrombin receptor, and another that is stimulated by higher concentrations of α-thrombin and by γ-thrombin and does not require the thrombin exosite for activation. Both pathways are blocked by a thrombin active site inhibitor.</description><identifier>ISSN: 0006-291X</identifier><identifier>EISSN: 1090-2104</identifier><identifier>DOI: 10.1016/0006-291X(91)91238-8</identifier><identifier>PMID: 1755847</identifier><identifier>CODEN: BBRCA9</identifier><language>eng</language><publisher>San Diego, CA: Elsevier Inc</publisher><subject>Amino Acid Sequence ; Biological and medical sciences ; Blood coagulation. Blood cells ; Drug Tolerance ; Fundamental and applied biological sciences. Psychology ; Humans ; Molecular and cellular biology ; Molecular Sequence Data ; Peptide Fragments - chemistry ; Peptide Fragments - pharmacology ; Peptides - pharmacology ; Platelet ; Platelet Activation - drug effects ; Signal Transduction ; Thrombin - antagonists & inhibitors ; Thrombin - pharmacology</subject><ispartof>Biochemical and biophysical research communications, 1991-12, Vol.181 (2), p.636-643</ispartof><rights>1991</rights><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-dec0ca130b32319e673493bc06646a9c5a10689db48a9d5bf16bb4d3961b75c23</citedby><cites>FETCH-LOGICAL-c386t-dec0ca130b32319e673493bc06646a9c5a10689db48a9d5bf16bb4d3961b75c23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/0006291X91912388$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=5050742$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1755847$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Seiler, Steven M.</creatorcontrib><creatorcontrib>Goldenberg, Harold J.</creatorcontrib><creatorcontrib>Michel, Inge M.</creatorcontrib><creatorcontrib>Hunt, John T.</creatorcontrib><creatorcontrib>Zavoico, George B.</creatorcontrib><title>Multiple pathways of thrombin-induced platelet activation differentiated by desensitization and a thrombin exosite inhibitor</title><title>Biochemical and biophysical research communications</title><addtitle>Biochem Biophys Res Commun</addtitle><description>Recently a thrombin receptor with a unique mechanism of activation was cloned from a megakaryocyte-like cell line (Vu et al., Cell
64
:1057–1068, 1991). Thrombin cleaves a portion of this receptor creating a new N-terminus that acts as a “tethered-ligand” to activate the receptor. A thrombin receptor activating peptide (SFLLRNPNDKYEPF) homologous to the new N-terminus was shown to activate platelets. We synthesized this peptide and demonstrated that it desensitized platelets to activation by low concentrations of α-thrombin but not γ-thrombin. We also synthesized a thrombin exosite inhibitor (BMS 180742) that inhibited platelet aggregation induced by low, but not high, concentrations of α-thrombin. In contrast, a thrombin active site inhibitor, Nα-(2-naphthylsulfonyl-glycyl)-D,L-amidinophenylalanylpiperidide, competitively inhibited thrombin-induced platelet aggregation. We conclude that thrombin-induced platelet activation is mediated by at least two pathways: one activated by low concentrations of α-thrombin and blocked by a thrombin exosite inhibitor that appears to be coupled to the “tethered-ligand” thrombin receptor, and another that is stimulated by higher concentrations of α-thrombin and by γ-thrombin and does not require the thrombin exosite for activation. Both pathways are blocked by a thrombin active site inhibitor.</description><subject>Amino Acid Sequence</subject><subject>Biological and medical sciences</subject><subject>Blood coagulation. Blood cells</subject><subject>Drug Tolerance</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>Molecular and cellular biology</subject><subject>Molecular Sequence Data</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - pharmacology</subject><subject>Peptides - pharmacology</subject><subject>Platelet</subject><subject>Platelet Activation - drug effects</subject><subject>Signal Transduction</subject><subject>Thrombin - antagonists & inhibitors</subject><subject>Thrombin - pharmacology</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1991</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE2r1DAUhoMo1_HqP1DIQkQX1ZymTZvNBbn4BVfcKLgL-ThljnTSMUmvjvjj7dhh3Lk6i_d5Xw4PY49BvAQB6pUQQlW1hq_PNbzQUMu-6u-wDQgtqhpEc5dtzsh99iDnb0IANEpfsAvo2rZvug37_XEeC-1H5Htbtj_sIfNp4GWbpp2jWFEMs8fA96MtOGLh1he6tYWmyAMNAyaMhZYscHfgATPGTIV-rYSNgdvzGMef0xIip7glR2VKD9m9wY4ZH53uJfvy9s3n6_fVzad3H65f31Re9qpUAb3wFqRwspagUXWy0dJ5oVSjrPatBaF6HVzTWx1aN4ByrglSK3Bd62t5yZ6tu_s0fZ8xF7Oj7HEcbcRpzqar205qaBewWUGfppwTDmafaGfTwYAwR-nmaNQcjRoN5q900y-1J6f92e0w_Cutlpf86Sm32dtxSDZ6ymesFa3omuObVyuGi4tbwmSyJ4yLf0roiwkT_f-PP4ZDoO4</recordid><startdate>19911216</startdate><enddate>19911216</enddate><creator>Seiler, Steven M.</creator><creator>Goldenberg, Harold J.</creator><creator>Michel, Inge M.</creator><creator>Hunt, John T.</creator><creator>Zavoico, George B.</creator><general>Elsevier Inc</general><general>Elsevier</general><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>7X8</scope></search><sort><creationdate>19911216</creationdate><title>Multiple pathways of thrombin-induced platelet activation differentiated by desensitization and a thrombin exosite inhibitor</title><author>Seiler, Steven M. ; Goldenberg, Harold J. ; Michel, Inge M. ; Hunt, John T. ; Zavoico, George B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-dec0ca130b32319e673493bc06646a9c5a10689db48a9d5bf16bb4d3961b75c23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1991</creationdate><topic>Amino Acid Sequence</topic><topic>Biological and medical sciences</topic><topic>Blood coagulation. Blood cells</topic><topic>Drug Tolerance</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Humans</topic><topic>Molecular and cellular biology</topic><topic>Molecular Sequence Data</topic><topic>Peptide Fragments - chemistry</topic><topic>Peptide Fragments - pharmacology</topic><topic>Peptides - pharmacology</topic><topic>Platelet</topic><topic>Platelet Activation - drug effects</topic><topic>Signal Transduction</topic><topic>Thrombin - antagonists & inhibitors</topic><topic>Thrombin - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Seiler, Steven M.</creatorcontrib><creatorcontrib>Goldenberg, Harold J.</creatorcontrib><creatorcontrib>Michel, Inge M.</creatorcontrib><creatorcontrib>Hunt, John T.</creatorcontrib><creatorcontrib>Zavoico, George B.</creatorcontrib><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>MEDLINE - Academic</collection><jtitle>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Seiler, Steven M.</au><au>Goldenberg, Harold J.</au><au>Michel, Inge M.</au><au>Hunt, John T.</au><au>Zavoico, George B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Multiple pathways of thrombin-induced platelet activation differentiated by desensitization and a thrombin exosite inhibitor</atitle><jtitle>Biochemical and biophysical research communications</jtitle><addtitle>Biochem Biophys Res Commun</addtitle><date>1991-12-16</date><risdate>1991</risdate><volume>181</volume><issue>2</issue><spage>636</spage><epage>643</epage><pages>636-643</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><coden>BBRCA9</coden><abstract>Recently a thrombin receptor with a unique mechanism of activation was cloned from a megakaryocyte-like cell line (Vu et al., Cell
64
:1057–1068, 1991). Thrombin cleaves a portion of this receptor creating a new N-terminus that acts as a “tethered-ligand” to activate the receptor. A thrombin receptor activating peptide (SFLLRNPNDKYEPF) homologous to the new N-terminus was shown to activate platelets. We synthesized this peptide and demonstrated that it desensitized platelets to activation by low concentrations of α-thrombin but not γ-thrombin. We also synthesized a thrombin exosite inhibitor (BMS 180742) that inhibited platelet aggregation induced by low, but not high, concentrations of α-thrombin. In contrast, a thrombin active site inhibitor, Nα-(2-naphthylsulfonyl-glycyl)-D,L-amidinophenylalanylpiperidide, competitively inhibited thrombin-induced platelet aggregation. We conclude that thrombin-induced platelet activation is mediated by at least two pathways: one activated by low concentrations of α-thrombin and blocked by a thrombin exosite inhibitor that appears to be coupled to the “tethered-ligand” thrombin receptor, and another that is stimulated by higher concentrations of α-thrombin and by γ-thrombin and does not require the thrombin exosite for activation. Both pathways are blocked by a thrombin active site inhibitor.</abstract><cop>San Diego, CA</cop><pub>Elsevier Inc</pub><pmid>1755847</pmid><doi>10.1016/0006-291X(91)91238-8</doi><tpages>8</tpages></addata></record> |
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| ispartof | Biochemical and biophysical research communications, 1991-12, Vol.181 (2), p.636-643 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Amino Acid Sequence Biological and medical sciences Blood coagulation. Blood cells Drug Tolerance Fundamental and applied biological sciences. Psychology Humans Molecular and cellular biology Molecular Sequence Data Peptide Fragments - chemistry Peptide Fragments - pharmacology Peptides - pharmacology Platelet Platelet Activation - drug effects Signal Transduction Thrombin - antagonists & inhibitors Thrombin - pharmacology |
| title | Multiple pathways of thrombin-induced platelet activation differentiated by desensitization and a thrombin exosite inhibitor |
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