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ARF6-Dependent Regulation of P2Y Receptor Traffic and Function in Human Platelets / Venkat, Kanamarlapudi; Sian-eleri, Owens

PLoS ONE, Volume: 7, Issue: 8, Start page: e43532

Swansesa University Authors: Venkat, Kanamarlapudi, Sian-eleri, Owens

Abstract

Adenosine diphosphate (ADP) is a critical regulator of platelet activation, mediating its actions through two G protein-coupled receptors, the P2Y1 and P2Y12 purinoceptors. Recently, we demonstrated that P2Y1 and P2Y12 purinoceptor activities are rapidly and reversibly modulated in human platelets,...

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Published in: PLoS ONE
ISSN: 1932-6203
Published: 2012
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URI: https://cronfa.swan.ac.uk/Record/cronfa12399
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spelling 2019-06-12T16:10:38.6268653 v2 12399 2012-08-23 ARF6-Dependent Regulation of P2Y Receptor Traffic and Function in Human Platelets 63741801137148abfa4c00cd547dcdfa 0000-0002-8739-1483 Venkat Kanamarlapudi Venkat Kanamarlapudi true false 721deb4604d122019244cfdf08820cbe 0000-0003-1806-5235 Sian-eleri Owens Sian-eleri Owens true false 2012-08-23 BMS Adenosine diphosphate (ADP) is a critical regulator of platelet activation, mediating its actions through two G protein-coupled receptors, the P2Y1 and P2Y12 purinoceptors. Recently, we demonstrated that P2Y1 and P2Y12 purinoceptor activities are rapidly and reversibly modulated in human platelets, revealing that the underlying mechanism requires receptor internalization and subsequent trafficking as an essential part of this process. In this study we investigated the role of the small GTP-binding protein ADP ribosylation factor 6 (ARF6) in the internalization and function of P2Y1 and P2Y12 purinoceptors in human platelets. ARF6 has been implicated in the internalization of a number of GPCRs, although its precise molecular mechanism in this process remains unclear. In this study we show that activation of either P2Y1 or P2Y12 purinoceptors can stimulate ARF6 activity. Further blockade of ARF6 function either in cell lines or human platelets blocks P2Y purinoceptor internalization. This blockade of receptor internalization attenuates receptor resensitization. Furthermore, we demonstrate that Nm23-H1, a nucleoside diphosphate (NDP) kinase regulated by ARF6 which facilitates dynamin-dependent fission of coated vesicles during endocytosis, is also required for P2Y purinoceptor internalization. These data describe a novel function of ARF6 in the internalization of P2Y purinoceptors and demonstrate the integral importance of this small GTPase upon platelet ADP receptor function. Journal Article PLoS ONE 7 8 e43532 1932-6203 16 8 2012 2012-08-16 10.1371/journal.pone.0043532 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0043532 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2019-06-12T16:10:38.6268653 2012-08-23T15:44:10.0002768 Swansea University Medical School Medicine Venkat Kanamarlapudi 0000-0002-8739-1483 1 Sian E Owens 2 Keya Saha 3 Robert J Pope 4 Stuart J Mundell 5 Sian-eleri Owens 0000-0003-1806-5235 6 0012399-12062019160948.PDF journal.pone.0043532.PDF 2019-06-12T16:09:48.7130000 Output 1612943 application/pdf Version of Record true 2019-06-12T00:00:00.0000000 true eng
title ARF6-Dependent Regulation of P2Y Receptor Traffic and Function in Human Platelets
spellingShingle ARF6-Dependent Regulation of P2Y Receptor Traffic and Function in Human Platelets
Venkat, Kanamarlapudi
Sian-eleri, Owens
title_short ARF6-Dependent Regulation of P2Y Receptor Traffic and Function in Human Platelets
title_full ARF6-Dependent Regulation of P2Y Receptor Traffic and Function in Human Platelets
title_fullStr ARF6-Dependent Regulation of P2Y Receptor Traffic and Function in Human Platelets
title_full_unstemmed ARF6-Dependent Regulation of P2Y Receptor Traffic and Function in Human Platelets
title_sort ARF6-Dependent Regulation of P2Y Receptor Traffic and Function in Human Platelets
author_id_str_mv 63741801137148abfa4c00cd547dcdfa
721deb4604d122019244cfdf08820cbe
author_id_fullname_str_mv 63741801137148abfa4c00cd547dcdfa_***_Venkat, Kanamarlapudi
721deb4604d122019244cfdf08820cbe_***_Sian-eleri, Owens
author Venkat, Kanamarlapudi
Sian-eleri, Owens
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publishDate 2012
institution Swansea University
issn 1932-6203
doi_str_mv 10.1371/journal.pone.0043532
college_str Swansea University Medical School
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hierarchy_top_title Swansea University Medical School
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hierarchy_parent_title Swansea University Medical School
department_str Medicine{{{_:::_}}}Swansea University Medical School{{{_:::_}}}Medicine
url http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0043532
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description Adenosine diphosphate (ADP) is a critical regulator of platelet activation, mediating its actions through two G protein-coupled receptors, the P2Y1 and P2Y12 purinoceptors. Recently, we demonstrated that P2Y1 and P2Y12 purinoceptor activities are rapidly and reversibly modulated in human platelets, revealing that the underlying mechanism requires receptor internalization and subsequent trafficking as an essential part of this process. In this study we investigated the role of the small GTP-binding protein ADP ribosylation factor 6 (ARF6) in the internalization and function of P2Y1 and P2Y12 purinoceptors in human platelets. ARF6 has been implicated in the internalization of a number of GPCRs, although its precise molecular mechanism in this process remains unclear. In this study we show that activation of either P2Y1 or P2Y12 purinoceptors can stimulate ARF6 activity. Further blockade of ARF6 function either in cell lines or human platelets blocks P2Y purinoceptor internalization. This blockade of receptor internalization attenuates receptor resensitization. Furthermore, we demonstrate that Nm23-H1, a nucleoside diphosphate (NDP) kinase regulated by ARF6 which facilitates dynamin-dependent fission of coated vesicles during endocytosis, is also required for P2Y purinoceptor internalization. These data describe a novel function of ARF6 in the internalization of P2Y purinoceptors and demonstrate the integral importance of this small GTPase upon platelet ADP receptor function.
published_date 2012-08-16T03:25:40Z
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