Role of GRK6 in the Regulation of Platelet Activation through Selective G Protein-Coupled Receptor (GPCR) Desensitization
Platelet G protein-coupled receptors (GPCRs) regulate platelet function by mediating the response to various agonists, including adenosine diphosphate (ADP), thromboxane A(2), and thrombin. Although GPCR kinases (GRKs) are considered to have the crucial roles in most GPCR functions, little is known...
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| Veröffentlicht in: | International journal of molecular sciences 2020-05, Vol.21 (11), p.3932, Article 3932 |
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| description | Platelet G protein-coupled receptors (GPCRs) regulate platelet function by mediating the response to various agonists, including adenosine diphosphate (ADP), thromboxane A(2), and thrombin. Although GPCR kinases (GRKs) are considered to have the crucial roles in most GPCR functions, little is known regarding the regulation of GPCR signaling and mechanisms of GPCR desensitization by GRKs in platelets. In this study, we investigated the functional role of GRK6 and the molecular basis for regulation of specific GPCR desensitization by GRK6 in platelets. We used GRK6 knockout mice to evaluate the functional role of GRK6 in platelet activation. Platelet aggregation, dense- and alpha-granule secretion, and fibrinogen receptor activation induced by 2-MeSADP, U46619, thrombin, and AYPGKF were significantly potentiated in GRK6(-/-) platelets compared to the wild-type (WT) platelets. However, collagen-related peptide (CRP)-induced platelet aggregation and secretion were not affected in GRK6(-/-) platelets. Interestingly, platelet aggregation induced by co-stimulation of serotonin and epinephrine which activate G(q)-coupled 5HT(2A) and G(z)-coupled alpha(2A) adrenergic receptors, respectively, was not affected in GRK6(-/-) platelets, suggesting that GRK6 was involved in specific GPCR regulation. In addition, platelet aggregation in response to the second challenge of ADP and AYPGKF was restored in GRK6(-/-) platelets whereas re-stimulation of the agonist failed to induce aggregation in WT platelets, indicating that GRK6 contributed to P2Y(1), P2Y(12), and PAR4 receptor desensitization. Furthermore, 2-MeSADP-induced Akt phosphorylation and AYPGKF-induced Akt, extracellular signal-related kinase (ERK), and protein kinase C delta (PKC delta) phosphorylation were significantly potentiated in GRK6(-/-) platelets. Finally, GRK6(-/-) mice exhibited an enhanced and stable thrombus formation after FeCl3 injury to the carotid artery and shorter tail bleeding times, indicating that GRK6(-/-) mice were more susceptible to thrombosis and hemostasis. We conclude that GRK6 plays an important role in regulating platelet functional responses and thrombus formation through selective GPCR desensitization. |
| doi_str_mv | 10.3390/ijms21113932 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_crossref_primary_10_3390_ijms21113932</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><doaj_id>oai_doaj_org_article_87403c45b4204915aeed863029923638</doaj_id><sourcerecordid>2409416418</sourcerecordid><originalsourceid>FETCH-LOGICAL-c478t-b8a3bcdeb9214e4081c1cbfec81beca1adf3c99456571bcb2c324923219fe5303</originalsourceid><addsrcrecordid>eNqNkktvEzEQgFcIREvhxhlZ4lIEC37twxekaguhohJRgLPl9c4mjjZ2sL2tyq_HyZYo5YR8sDXz-dOMPVn2kuD3jAn8waw3gRJCmGD0UXZKOKU5xmX1-Oh8kj0LYY0xZbQQT7MTRnld0pKcZncLNwByPZotvpbIWBRXgBawHAcVjbO7zDwdYYCILnQ0N1M4rrwblyv0PSV2UUAzNPcugrF548btAF2yaNhG59H5bN4s3qBLCGCDieb33vE8e9KrIcCL-_0s-_n504_mS379bXbVXFznmld1zNtasVZ30ApKOHBcE01024OuSQtaEdX1TAvBi7KoSKtbqlNzIjVKRA8Fw-wsu5q8nVNrufVmo_yddMrIfcD5pVQ-Gj2ArCuOmeZFyynmghQKoKtLhqlIwpLVyfVxcm3HdgOdBhu9Gh5IH2asWcmlu5EVI5SUIgnO7wXe_RohRLkxQcMwKAtuDJJyLEhanCf09T_o2o3epqfaU5yUnOwqejdR2rsQPPSHYgiWu_mQx_OR8FfHDRzgvwORgHoCbqF1fdAGrIYDhjEuOOMYM4xTkY2J-69MP25juvr2_6-yPwAO1no</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2409416418</pqid></control><display><type>article</type><title>Role of GRK6 in the Regulation of Platelet Activation through Selective G Protein-Coupled Receptor (GPCR) Desensitization</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>Web of Science - Science Citation Index Expanded - 2020<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /></source><source>PubMed Central</source><creator>Chaudhary, Preeti Kumari ; Kim, Sanggu ; Jee, Youngheun ; Lee, Seung-Hun ; Park, Kyung-Mee ; Kim, Soochong</creator><creatorcontrib>Chaudhary, Preeti Kumari ; Kim, Sanggu ; Jee, Youngheun ; Lee, Seung-Hun ; Park, Kyung-Mee ; Kim, Soochong</creatorcontrib><description>Platelet G protein-coupled receptors (GPCRs) regulate platelet function by mediating the response to various agonists, including adenosine diphosphate (ADP), thromboxane A(2), and thrombin. Although GPCR kinases (GRKs) are considered to have the crucial roles in most GPCR functions, little is known regarding the regulation of GPCR signaling and mechanisms of GPCR desensitization by GRKs in platelets. In this study, we investigated the functional role of GRK6 and the molecular basis for regulation of specific GPCR desensitization by GRK6 in platelets. We used GRK6 knockout mice to evaluate the functional role of GRK6 in platelet activation. Platelet aggregation, dense- and alpha-granule secretion, and fibrinogen receptor activation induced by 2-MeSADP, U46619, thrombin, and AYPGKF were significantly potentiated in GRK6(-/-) platelets compared to the wild-type (WT) platelets. However, collagen-related peptide (CRP)-induced platelet aggregation and secretion were not affected in GRK6(-/-) platelets. Interestingly, platelet aggregation induced by co-stimulation of serotonin and epinephrine which activate G(q)-coupled 5HT(2A) and G(z)-coupled alpha(2A) adrenergic receptors, respectively, was not affected in GRK6(-/-) platelets, suggesting that GRK6 was involved in specific GPCR regulation. In addition, platelet aggregation in response to the second challenge of ADP and AYPGKF was restored in GRK6(-/-) platelets whereas re-stimulation of the agonist failed to induce aggregation in WT platelets, indicating that GRK6 contributed to P2Y(1), P2Y(12), and PAR4 receptor desensitization. Furthermore, 2-MeSADP-induced Akt phosphorylation and AYPGKF-induced Akt, extracellular signal-related kinase (ERK), and protein kinase C delta (PKC delta) phosphorylation were significantly potentiated in GRK6(-/-) platelets. Finally, GRK6(-/-) mice exhibited an enhanced and stable thrombus formation after FeCl3 injury to the carotid artery and shorter tail bleeding times, indicating that GRK6(-/-) mice were more susceptible to thrombosis and hemostasis. We conclude that GRK6 plays an important role in regulating platelet functional responses and thrombus formation through selective GPCR desensitization.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms21113932</identifier><identifier>PMID: 32486261</identifier><language>eng</language><publisher>BASEL: Mdpi</publisher><subject>15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology ; Activation ; Adenosine diphosphate ; Adenosine Diphosphate - analogs & derivatives ; Adenosine Diphosphate - metabolism ; Adenosine Diphosphate - pharmacology ; ADP ; Adrenergic receptors ; Agonists ; AKT protein ; Animals ; Binding sites ; Biochemistry & Molecular Biology ; Blood Platelets - metabolism ; Chemistry ; Chemistry, Multidisciplinary ; Collagen ; Desensitization ; Epinephrine ; Extracellular signal-regulated kinase ; Female ; Ferric chloride ; Fibrinogen ; G protein-coupled receptors ; G-Protein-Coupled Receptor Kinases - metabolism ; Gene Expression Regulation ; Glycoproteins ; GPCR ; GRK6 ; Hemostasis ; Hemostatics ; Iron chlorides ; Kinases ; Life Sciences & Biomedicine ; Male ; Mice ; Mice, Knockout ; Oligopeptides - pharmacology ; PAR ; Phosphorylation ; Physical Sciences ; Platelet Activation ; Platelet Aggregation ; platelets ; Protein kinase ; Protein kinase C ; Proteins ; Receptor mechanisms ; Receptors (physiology) ; Receptors, G-Protein-Coupled - metabolism ; Science & Technology ; Secretion ; Serotonin ; Signal transduction ; Stimulation ; Thionucleotides - pharmacology ; Thrombin ; Thrombin - metabolism ; Thrombosis ; Thromboxane A2 ; Thromboxane A2 - metabolism</subject><ispartof>International journal of molecular sciences, 2020-05, Vol.21 (11), p.3932, Article 3932</ispartof><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>12</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000543400300194</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c478t-b8a3bcdeb9214e4081c1cbfec81beca1adf3c99456571bcb2c324923219fe5303</citedby><cites>FETCH-LOGICAL-c478t-b8a3bcdeb9214e4081c1cbfec81beca1adf3c99456571bcb2c324923219fe5303</cites><orcidid>0000-0002-6244-0381</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312169/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312169/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,886,27929,27930,28253,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32486261$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chaudhary, Preeti Kumari</creatorcontrib><creatorcontrib>Kim, Sanggu</creatorcontrib><creatorcontrib>Jee, Youngheun</creatorcontrib><creatorcontrib>Lee, Seung-Hun</creatorcontrib><creatorcontrib>Park, Kyung-Mee</creatorcontrib><creatorcontrib>Kim, Soochong</creatorcontrib><title>Role of GRK6 in the Regulation of Platelet Activation through Selective G Protein-Coupled Receptor (GPCR) Desensitization</title><title>International journal of molecular sciences</title><addtitle>INT J MOL SCI</addtitle><addtitle>Int J Mol Sci</addtitle><description>Platelet G protein-coupled receptors (GPCRs) regulate platelet function by mediating the response to various agonists, including adenosine diphosphate (ADP), thromboxane A(2), and thrombin. Although GPCR kinases (GRKs) are considered to have the crucial roles in most GPCR functions, little is known regarding the regulation of GPCR signaling and mechanisms of GPCR desensitization by GRKs in platelets. In this study, we investigated the functional role of GRK6 and the molecular basis for regulation of specific GPCR desensitization by GRK6 in platelets. We used GRK6 knockout mice to evaluate the functional role of GRK6 in platelet activation. Platelet aggregation, dense- and alpha-granule secretion, and fibrinogen receptor activation induced by 2-MeSADP, U46619, thrombin, and AYPGKF were significantly potentiated in GRK6(-/-) platelets compared to the wild-type (WT) platelets. However, collagen-related peptide (CRP)-induced platelet aggregation and secretion were not affected in GRK6(-/-) platelets. Interestingly, platelet aggregation induced by co-stimulation of serotonin and epinephrine which activate G(q)-coupled 5HT(2A) and G(z)-coupled alpha(2A) adrenergic receptors, respectively, was not affected in GRK6(-/-) platelets, suggesting that GRK6 was involved in specific GPCR regulation. In addition, platelet aggregation in response to the second challenge of ADP and AYPGKF was restored in GRK6(-/-) platelets whereas re-stimulation of the agonist failed to induce aggregation in WT platelets, indicating that GRK6 contributed to P2Y(1), P2Y(12), and PAR4 receptor desensitization. Furthermore, 2-MeSADP-induced Akt phosphorylation and AYPGKF-induced Akt, extracellular signal-related kinase (ERK), and protein kinase C delta (PKC delta) phosphorylation were significantly potentiated in GRK6(-/-) platelets. Finally, GRK6(-/-) mice exhibited an enhanced and stable thrombus formation after FeCl3 injury to the carotid artery and shorter tail bleeding times, indicating that GRK6(-/-) mice were more susceptible to thrombosis and hemostasis. We conclude that GRK6 plays an important role in regulating platelet functional responses and thrombus formation through selective GPCR desensitization.</description><subject>15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology</subject><subject>Activation</subject><subject>Adenosine diphosphate</subject><subject>Adenosine Diphosphate - analogs & derivatives</subject><subject>Adenosine Diphosphate - metabolism</subject><subject>Adenosine Diphosphate - pharmacology</subject><subject>ADP</subject><subject>Adrenergic receptors</subject><subject>Agonists</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Binding sites</subject><subject>Biochemistry & Molecular Biology</subject><subject>Blood Platelets - metabolism</subject><subject>Chemistry</subject><subject>Chemistry, Multidisciplinary</subject><subject>Collagen</subject><subject>Desensitization</subject><subject>Epinephrine</subject><subject>Extracellular signal-regulated kinase</subject><subject>Female</subject><subject>Ferric chloride</subject><subject>Fibrinogen</subject><subject>G protein-coupled receptors</subject><subject>G-Protein-Coupled Receptor Kinases - metabolism</subject><subject>Gene Expression Regulation</subject><subject>Glycoproteins</subject><subject>GPCR</subject><subject>GRK6</subject><subject>Hemostasis</subject><subject>Hemostatics</subject><subject>Iron chlorides</subject><subject>Kinases</subject><subject>Life Sciences & Biomedicine</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Oligopeptides - pharmacology</subject><subject>PAR</subject><subject>Phosphorylation</subject><subject>Physical Sciences</subject><subject>Platelet Activation</subject><subject>Platelet Aggregation</subject><subject>platelets</subject><subject>Protein kinase</subject><subject>Protein kinase C</subject><subject>Proteins</subject><subject>Receptor mechanisms</subject><subject>Receptors (physiology)</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Science & Technology</subject><subject>Secretion</subject><subject>Serotonin</subject><subject>Signal transduction</subject><subject>Stimulation</subject><subject>Thionucleotides - pharmacology</subject><subject>Thrombin</subject><subject>Thrombin - metabolism</subject><subject>Thrombosis</subject><subject>Thromboxane A2</subject><subject>Thromboxane A2 - metabolism</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>AOWDO</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><sourceid>DOA</sourceid><recordid>eNqNkktvEzEQgFcIREvhxhlZ4lIEC37twxekaguhohJRgLPl9c4mjjZ2sL2tyq_HyZYo5YR8sDXz-dOMPVn2kuD3jAn8waw3gRJCmGD0UXZKOKU5xmX1-Oh8kj0LYY0xZbQQT7MTRnld0pKcZncLNwByPZotvpbIWBRXgBawHAcVjbO7zDwdYYCILnQ0N1M4rrwblyv0PSV2UUAzNPcugrF548btAF2yaNhG59H5bN4s3qBLCGCDieb33vE8e9KrIcCL-_0s-_n504_mS379bXbVXFznmld1zNtasVZ30ApKOHBcE01024OuSQtaEdX1TAvBi7KoSKtbqlNzIjVKRA8Fw-wsu5q8nVNrufVmo_yddMrIfcD5pVQ-Gj2ArCuOmeZFyynmghQKoKtLhqlIwpLVyfVxcm3HdgOdBhu9Gh5IH2asWcmlu5EVI5SUIgnO7wXe_RohRLkxQcMwKAtuDJJyLEhanCf09T_o2o3epqfaU5yUnOwqejdR2rsQPPSHYgiWu_mQx_OR8FfHDRzgvwORgHoCbqF1fdAGrIYDhjEuOOMYM4xTkY2J-69MP25juvr2_6-yPwAO1no</recordid><startdate>20200530</startdate><enddate>20200530</enddate><creator>Chaudhary, Preeti Kumari</creator><creator>Kim, Sanggu</creator><creator>Jee, Youngheun</creator><creator>Lee, Seung-Hun</creator><creator>Park, Kyung-Mee</creator><creator>Kim, Soochong</creator><general>Mdpi</general><general>MDPI AG</general><general>MDPI</general><scope>AOWDO</scope><scope>BLEPL</scope><scope>DTL</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-6244-0381</orcidid></search><sort><creationdate>20200530</creationdate><title>Role of GRK6 in the Regulation of Platelet Activation through Selective G Protein-Coupled Receptor (GPCR) Desensitization</title><author>Chaudhary, Preeti Kumari ; Kim, Sanggu ; Jee, Youngheun ; Lee, Seung-Hun ; Park, Kyung-Mee ; Kim, Soochong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-b8a3bcdeb9214e4081c1cbfec81beca1adf3c99456571bcb2c324923219fe5303</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology</topic><topic>Activation</topic><topic>Adenosine diphosphate</topic><topic>Adenosine Diphosphate - analogs & derivatives</topic><topic>Adenosine Diphosphate - metabolism</topic><topic>Adenosine Diphosphate - pharmacology</topic><topic>ADP</topic><topic>Adrenergic receptors</topic><topic>Agonists</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Binding sites</topic><topic>Biochemistry & Molecular Biology</topic><topic>Blood Platelets - metabolism</topic><topic>Chemistry</topic><topic>Chemistry, Multidisciplinary</topic><topic>Collagen</topic><topic>Desensitization</topic><topic>Epinephrine</topic><topic>Extracellular signal-regulated kinase</topic><topic>Female</topic><topic>Ferric chloride</topic><topic>Fibrinogen</topic><topic>G protein-coupled receptors</topic><topic>G-Protein-Coupled Receptor Kinases - metabolism</topic><topic>Gene Expression Regulation</topic><topic>Glycoproteins</topic><topic>GPCR</topic><topic>GRK6</topic><topic>Hemostasis</topic><topic>Hemostatics</topic><topic>Iron chlorides</topic><topic>Kinases</topic><topic>Life Sciences & Biomedicine</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Oligopeptides - pharmacology</topic><topic>PAR</topic><topic>Phosphorylation</topic><topic>Physical Sciences</topic><topic>Platelet Activation</topic><topic>Platelet Aggregation</topic><topic>platelets</topic><topic>Protein kinase</topic><topic>Protein kinase C</topic><topic>Proteins</topic><topic>Receptor mechanisms</topic><topic>Receptors (physiology)</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Science & Technology</topic><topic>Secretion</topic><topic>Serotonin</topic><topic>Signal transduction</topic><topic>Stimulation</topic><topic>Thionucleotides - pharmacology</topic><topic>Thrombin</topic><topic>Thrombin - metabolism</topic><topic>Thrombosis</topic><topic>Thromboxane A2</topic><topic>Thromboxane A2 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chaudhary, Preeti Kumari</creatorcontrib><creatorcontrib>Kim, Sanggu</creatorcontrib><creatorcontrib>Jee, Youngheun</creatorcontrib><creatorcontrib>Lee, Seung-Hun</creatorcontrib><creatorcontrib>Park, Kyung-Mee</creatorcontrib><creatorcontrib>Kim, Soochong</creatorcontrib><collection>Web of Science - Science Citation Index Expanded - 2020</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chaudhary, Preeti Kumari</au><au>Kim, Sanggu</au><au>Jee, Youngheun</au><au>Lee, Seung-Hun</au><au>Park, Kyung-Mee</au><au>Kim, Soochong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of GRK6 in the Regulation of Platelet Activation through Selective G Protein-Coupled Receptor (GPCR) Desensitization</atitle><jtitle>International journal of molecular sciences</jtitle><stitle>INT J MOL SCI</stitle><addtitle>Int J Mol Sci</addtitle><date>2020-05-30</date><risdate>2020</risdate><volume>21</volume><issue>11</issue><spage>3932</spage><pages>3932-</pages><artnum>3932</artnum><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Platelet G protein-coupled receptors (GPCRs) regulate platelet function by mediating the response to various agonists, including adenosine diphosphate (ADP), thromboxane A(2), and thrombin. Although GPCR kinases (GRKs) are considered to have the crucial roles in most GPCR functions, little is known regarding the regulation of GPCR signaling and mechanisms of GPCR desensitization by GRKs in platelets. In this study, we investigated the functional role of GRK6 and the molecular basis for regulation of specific GPCR desensitization by GRK6 in platelets. We used GRK6 knockout mice to evaluate the functional role of GRK6 in platelet activation. Platelet aggregation, dense- and alpha-granule secretion, and fibrinogen receptor activation induced by 2-MeSADP, U46619, thrombin, and AYPGKF were significantly potentiated in GRK6(-/-) platelets compared to the wild-type (WT) platelets. However, collagen-related peptide (CRP)-induced platelet aggregation and secretion were not affected in GRK6(-/-) platelets. Interestingly, platelet aggregation induced by co-stimulation of serotonin and epinephrine which activate G(q)-coupled 5HT(2A) and G(z)-coupled alpha(2A) adrenergic receptors, respectively, was not affected in GRK6(-/-) platelets, suggesting that GRK6 was involved in specific GPCR regulation. In addition, platelet aggregation in response to the second challenge of ADP and AYPGKF was restored in GRK6(-/-) platelets whereas re-stimulation of the agonist failed to induce aggregation in WT platelets, indicating that GRK6 contributed to P2Y(1), P2Y(12), and PAR4 receptor desensitization. Furthermore, 2-MeSADP-induced Akt phosphorylation and AYPGKF-induced Akt, extracellular signal-related kinase (ERK), and protein kinase C delta (PKC delta) phosphorylation were significantly potentiated in GRK6(-/-) platelets. Finally, GRK6(-/-) mice exhibited an enhanced and stable thrombus formation after FeCl3 injury to the carotid artery and shorter tail bleeding times, indicating that GRK6(-/-) mice were more susceptible to thrombosis and hemostasis. We conclude that GRK6 plays an important role in regulating platelet functional responses and thrombus formation through selective GPCR desensitization.</abstract><cop>BASEL</cop><pub>Mdpi</pub><pmid>32486261</pmid><doi>10.3390/ijms21113932</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-6244-0381</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_crossref_primary_10_3390_ijms21113932 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; MDPI - Multidisciplinary Digital Publishing Institute; Web of Science - Science Citation Index Expanded - 2020<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; PubMed Central |
| subjects | 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology Activation Adenosine diphosphate Adenosine Diphosphate - analogs & derivatives Adenosine Diphosphate - metabolism Adenosine Diphosphate - pharmacology ADP Adrenergic receptors Agonists AKT protein Animals Binding sites Biochemistry & Molecular Biology Blood Platelets - metabolism Chemistry Chemistry, Multidisciplinary Collagen Desensitization Epinephrine Extracellular signal-regulated kinase Female Ferric chloride Fibrinogen G protein-coupled receptors G-Protein-Coupled Receptor Kinases - metabolism Gene Expression Regulation Glycoproteins GPCR GRK6 Hemostasis Hemostatics Iron chlorides Kinases Life Sciences & Biomedicine Male Mice Mice, Knockout Oligopeptides - pharmacology PAR Phosphorylation Physical Sciences Platelet Activation Platelet Aggregation platelets Protein kinase Protein kinase C Proteins Receptor mechanisms Receptors (physiology) Receptors, G-Protein-Coupled - metabolism Science & Technology Secretion Serotonin Signal transduction Stimulation Thionucleotides - pharmacology Thrombin Thrombin - metabolism Thrombosis Thromboxane A2 Thromboxane A2 - metabolism |
| title | Role of GRK6 in the Regulation of Platelet Activation through Selective G Protein-Coupled Receptor (GPCR) Desensitization |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-14T04%3A32%3A32IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Role%20of%20GRK6%20in%20the%20Regulation%20of%20Platelet%20Activation%20through%20Selective%20G%20Protein-Coupled%20Receptor%20(GPCR)%20Desensitization&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.au=Chaudhary,%20Preeti%20Kumari&rft.date=2020-05-30&rft.volume=21&rft.issue=11&rft.spage=3932&rft.pages=3932-&rft.artnum=3932&rft.issn=1422-0067&rft.eissn=1422-0067&rft_id=info:doi/10.3390/ijms21113932&rft_dat=%3Cproquest_cross%3E2409416418%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2409416418&rft_id=info:pmid/32486261&rft_doaj_id=oai_doaj_org_article_87403c45b4204915aeed863029923638&rfr_iscdi=true |