Document Detail

Differential endosomal sorting of a novel P2Y12 purinoreceptor mutant.
MedLine Citation:
PMID:  23387322     Owner:  NLM     Status:  MEDLINE    
P2Y12 receptor internalization and recycling play an essential role in ADP-induced platelet activation. Recently, we identified a patient with a mild bleeding disorder carrying a heterozygous mutation of P2Y12 (P341A) whose P2Y12 receptor recycling was significantly compromised. Using human cell line models, we identified key proteins regulating wild-type (WT) P2Y12 recycling and investigated P2Y12 -P341A receptor traffic. Treatment with ADP resulted in delayed Rab5-dependent internalization of P341A when compared with WT P2Y12 . While WT P2Y12 rapidly recycled back to the membrane via Rab4 and Rab11 recycling pathways, limited P341A recycling was observed, which relied upon Rab11 activity. Although minimal receptor degradation was evident, P341A was localized in Rab7-positive endosomes with considerable agonist-dependent accumulation in the trans-Golgi network (TGN). Rab7 activity is known to facilitate recruitment of retromer complex proteins to endosomes to transport cargo to the TGN. Here, we identified that P341A colocalized with Vps26; depletion of which blocked limited recycling and promoted receptor degradation. This study has identified key points of divergence in the endocytic traffic of P341A versus WT-P2Y12 . Given that these pathways are retained in human platelets, this research helps define the molecular mechanisms regulating P2Y12 receptor traffic and explain the compromised receptor function in the platelets of the P2Y12 -P341A-expressing patient.
Margaret R Cunningham; Shaista P Nisar; Alexandra E Cooke; Elizabeth D Emery; Stuart J Mundell
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-03-12
Journal Detail:
Title:  Traffic (Copenhagen, Denmark)     Volume:  14     ISSN:  1600-0854     ISO Abbreviation:  Traffic     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-09     Completed Date:  2013-12-18     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  100939340     Medline TA:  Traffic     Country:  England    
Other Details:
Languages:  eng     Pagination:  585-98     Citation Subset:  IM    
Copyright Information:
© 2013 John Wiley & Sons A/S.
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MeSH Terms
Adenosine Diphosphate / metabolism
Biological Transport
Blood Platelets / metabolism
Cell Line
Endosomes / metabolism*
Gene Expression Regulation*
HEK293 Cells
Mutant Proteins / metabolism
Plasmids / metabolism
Protein Structure, Tertiary
Receptors, Purinergic P2Y12 / metabolism*
rab GTP-Binding Proteins / metabolism
rab5 GTP-Binding Proteins / metabolism*
Grant Support
FS/11/49/28751//British Heart Foundation; G1000432//Medical Research Council; PG/09/091/28074//British Heart Foundation; RG/09/007/27917//British Heart Foundation
Reg. No./Substance:
0/Ligands; 0/Mutant Proteins; 0/Receptors, Purinergic P2Y12; 61D2G4IYVH/Adenosine Diphosphate; EC 3.6.1.-/rab GTP-Binding Proteins; EC 3.6.1.-/rab11 protein; EC GTP-Binding Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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