| Allosteric modulation of protease-activated receptor signaling. | |
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MedLine Citation:
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PMID: 22681248 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The protease-activated receptors (PARs) are G protein-coupled receptors (GPCRs) that are uniquely activated by proteolysis. PARs mediate hemostasis, thrombosis, inflammation, embryonic development and progression of certain malignant cancers. The family of PARs include four members: PAR1, PAR2, PAR3 and PAR4. PARs harbor a cryptic ligand sequence within their N-terminus that is exposed following proteolytic cleavage. The newly formed PAR Nterminus functions as a tethered ligand that binds intramolecularly to the receptor to trigger transmembrane signaling. This unique mechanism of activation would indicate that regardless of the activating protease, cleavage of PARs would unmask a tethered ligand sequence that would induce a similar active receptor conformation and signaling response. However, this is not the case. Recent studies demonstrate that PARs can be differentially activated by synthetic peptide agonists, proteases or through dimerization, that ultimately result in distinct cellular responses. In some cases, allosteric modulation of PARs involves compartmentalization in caveolae, plasma membrane microdomains enriched in cholesterol. Here, we discuss some mechanisms that lead to allosteric modulation of PAR signaling. |
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Authors:
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I Canto; U J K Soh; J Trejo |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review |
Journal Detail:
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Title: Mini reviews in medicinal chemistry Volume: 12 ISSN: 1875-5607 ISO Abbreviation: Mini Rev Med Chem Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-07-04 Completed Date: 2012-10-24 Revised Date: 2012-11-06 |
Medline Journal Info:
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Nlm Unique ID: 101094212 Medline TA: Mini Rev Med Chem Country: Netherlands |
Other Details:
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Languages: eng Pagination: 804-11 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, School of Medicine, University of California, San Diego, Biomedical Sciences Building, Room 3044A, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA. joanntrejo@ucsd.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Allosteric Regulation Cell Transformation, Neoplastic / metabolism Embryonic Development / physiology Hemostasis / drug effects, physiology Humans Peptides / pharmacology Protein Isoforms / metabolism Protein Multimerization Protein Structure, Tertiary Proteolysis / drug effects Receptors, Proteinase-Activated / metabolism* Signal Transduction / drug effects, physiology* Thrombin / metabolism* Thrombosis / metabolism, physiopathology |
| Grant Support | |
ID/Acronym/Agency:
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GM090689/GM/NIGMS NIH HHS; HL073328/HL/NHLBI NIH HHS; R01 GM090689/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Peptides; 0/Protein Isoforms; 0/Receptors, Proteinase-Activated; EC 3.4.21.5/Thrombin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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