Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization

Joseph N. McLaughlin, Myla M. Patterson, Asrar B. Malik

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

Thrombin activates endothelial cell signaling by cleaving the protease-activated receptor-1 (PAR1). However, the function of the apparently nonsignaling receptor PAR3 also expressed in endothelial cells is unknown. We demonstrate here the crucial role of PAR3 in potentiating the responsiveness of PAR1 to thrombin. We tested the hypothesis that PAR1/PAR3 heterodimerization and its effect in modifying G protein selectivity was responsible for PAR3 regulation of PAR1 sensitivity. Using bioluminescent resonance energy transfer-2, we showed that PAR1 had comparable dimerization affinity for PAR3 as for itself. We observed increased Gα13 coupling between the PAR1/3 heterodimer compared with the PAR1/1 homodimer. Moreover, knockdown of PAR3 moderated the PAR1-activated increase in endothelial permeability. These results demonstrate a role of PAR3 in allosterically regulating PAR1 signaling governing increased endothelial permeability. Because PAR3 is a critical determinant of PAR1 function, targeting of PAR3 may mitigate the effects of PAR1 in activating endothelial responses such as vascular inflammation.

Original languageEnglish (US)
Pages (from-to)5662-5667
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number13
DOIs
StatePublished - Mar 27 2007
Externally publishedYes

Fingerprint

PAR-1 Receptor
Dimerization
Thrombin
Permeability
protease-activated receptor 3
Endothelial Cells
Energy Transfer
GTP-Binding Proteins
Blood Vessels

Keywords

  • Endothelium
  • Functional selectivity
  • G protein
  • Signal transduction
  • Thrombin

ASJC Scopus subject areas

  • General

Cite this

Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization. / McLaughlin, Joseph N.; Patterson, Myla M.; Malik, Asrar B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 13, 27.03.2007, p. 5662-5667.

Research output: Contribution to journalArticle

@article{9af1796299a147e794c5efde65d38c78,
title = "Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization",
abstract = "Thrombin activates endothelial cell signaling by cleaving the protease-activated receptor-1 (PAR1). However, the function of the apparently nonsignaling receptor PAR3 also expressed in endothelial cells is unknown. We demonstrate here the crucial role of PAR3 in potentiating the responsiveness of PAR1 to thrombin. We tested the hypothesis that PAR1/PAR3 heterodimerization and its effect in modifying G protein selectivity was responsible for PAR3 regulation of PAR1 sensitivity. Using bioluminescent resonance energy transfer-2, we showed that PAR1 had comparable dimerization affinity for PAR3 as for itself. We observed increased Gα13 coupling between the PAR1/3 heterodimer compared with the PAR1/1 homodimer. Moreover, knockdown of PAR3 moderated the PAR1-activated increase in endothelial permeability. These results demonstrate a role of PAR3 in allosterically regulating PAR1 signaling governing increased endothelial permeability. Because PAR3 is a critical determinant of PAR1 function, targeting of PAR3 may mitigate the effects of PAR1 in activating endothelial responses such as vascular inflammation.",
keywords = "Endothelium, Functional selectivity, G protein, Signal transduction, Thrombin",
author = "McLaughlin, {Joseph N.} and Patterson, {Myla M.} and Malik, {Asrar B.}",
year = "2007",
month = "3",
day = "27",
doi = "10.1073/pnas.0700763104",
language = "English (US)",
volume = "104",
pages = "5662--5667",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "13",

}

TY - JOUR

T1 - Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization

AU - McLaughlin, Joseph N.

AU - Patterson, Myla M.

AU - Malik, Asrar B.

PY - 2007/3/27

Y1 - 2007/3/27

N2 - Thrombin activates endothelial cell signaling by cleaving the protease-activated receptor-1 (PAR1). However, the function of the apparently nonsignaling receptor PAR3 also expressed in endothelial cells is unknown. We demonstrate here the crucial role of PAR3 in potentiating the responsiveness of PAR1 to thrombin. We tested the hypothesis that PAR1/PAR3 heterodimerization and its effect in modifying G protein selectivity was responsible for PAR3 regulation of PAR1 sensitivity. Using bioluminescent resonance energy transfer-2, we showed that PAR1 had comparable dimerization affinity for PAR3 as for itself. We observed increased Gα13 coupling between the PAR1/3 heterodimer compared with the PAR1/1 homodimer. Moreover, knockdown of PAR3 moderated the PAR1-activated increase in endothelial permeability. These results demonstrate a role of PAR3 in allosterically regulating PAR1 signaling governing increased endothelial permeability. Because PAR3 is a critical determinant of PAR1 function, targeting of PAR3 may mitigate the effects of PAR1 in activating endothelial responses such as vascular inflammation.

AB - Thrombin activates endothelial cell signaling by cleaving the protease-activated receptor-1 (PAR1). However, the function of the apparently nonsignaling receptor PAR3 also expressed in endothelial cells is unknown. We demonstrate here the crucial role of PAR3 in potentiating the responsiveness of PAR1 to thrombin. We tested the hypothesis that PAR1/PAR3 heterodimerization and its effect in modifying G protein selectivity was responsible for PAR3 regulation of PAR1 sensitivity. Using bioluminescent resonance energy transfer-2, we showed that PAR1 had comparable dimerization affinity for PAR3 as for itself. We observed increased Gα13 coupling between the PAR1/3 heterodimer compared with the PAR1/1 homodimer. Moreover, knockdown of PAR3 moderated the PAR1-activated increase in endothelial permeability. These results demonstrate a role of PAR3 in allosterically regulating PAR1 signaling governing increased endothelial permeability. Because PAR3 is a critical determinant of PAR1 function, targeting of PAR3 may mitigate the effects of PAR1 in activating endothelial responses such as vascular inflammation.

KW - Endothelium

KW - Functional selectivity

KW - G protein

KW - Signal transduction

KW - Thrombin

UR - http://www.scopus.com/inward/record.url?scp=34248374907&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34248374907&partnerID=8YFLogxK

U2 - 10.1073/pnas.0700763104

DO - 10.1073/pnas.0700763104

M3 - Article

C2 - 17376866

AN - SCOPUS:34248374907

VL - 104

SP - 5662

EP - 5667

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 13

ER -