Molecular mechanisms regulating Proteinase-Activated Receptors (PARs)

Chandrabalan, Arundhasa; Ramachandran, Rithwik

doi:10.1111/febs.15829

Cited by 83Blood Coagulation and Thrombosis MechanismsReceptor Mechanisms and SignalingProtease and Inhibitor Mechanisms

Molecular mechanisms regulating Proteinase-Activated Receptors (PARs)

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Chandrabalan, Arundhasa, Ramachandran, Rithwik·2021·The FEBS Journal

DOI 10.1111/febs.15829

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Abstract

Proteinase‐activated receptors (PARs) are a four‐member family of G protein‐coupled receptors defined by their irreversible proteolytic mechanism of activation. PARs have emerged as important regulators of various physiological responses and are implicated in numerous pathological conditions. Importantly, PAR1 and PAR4 are critical regulators of platelet function, while PAR2 is well established as a driver of inflammatory responses. PAR‐targeted drug development efforts are therefore of great interest. In this review, we provide an overview of recent advances in our understanding of molecular mechanisms underlying PAR activation, effector interaction, and signaling. We also provide an overview of the diverse proteolytic enzymes that are now established as PAR regulators and describe the ability of different enzymes to elicit biased signaling through PARs. Finally, we highlight recent advances in the development of PAR‐targeted pharmacological agents and discuss recent structure–activity relationship studies.

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PAR-2 decreases autophagy through the PI3K/Akt/mTOR pathway in kidney cells.
“For instance, PAR-2 was shown to decrease autophagy through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in kidney cells [ 108 , 109 ].”
From Melanin's Journey from Melanocytes to Keratinocytes: Uncovering the Molecular Mechanisms of Melanin Transfer and Processing (2023) · cites this paper as [109]
The Concluding remarks (Fig. 4; page unavailable) describe PI3K/Akt as a PAR signaling pathway. They do not say that PAR2 decreases autophagy, identify mTOR in that pathway, or report this effect in kidney cells; searches for autophagy, mTOR, and kidney-related terms found no supporting passage. (LLM, conf=0.78)
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Authors: Chandrabalan, A., & Ramachandran, R.
Affiliations: Western University (CA)
Corresponding author: Ramachandran, Rithwik
ORCID: Chandrabalan, Arundhasa
Ramachandran, Rithwik
Venue: The FEBS Journal
Publisher: Wiley
Published: 2021-04
Volume: 288
Issue: 8
Pages: 2697-2726
ISSN: 1742-464X (ISSN-L)
1742-4658
DOI: 10.1111/febs.15829
OpenAlex: W3137465526
Cited by: 83
References: 238
Citations by year: 2026: 13 · 2025: 15 · 2024: 15 · 2023: 20 · 2022: 16 · 2021: 4
FWCI: 2.41
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 5 d)
Locations: FEBS Journal (publishedVersion)
PubMed (publishedVersion)
Funders: Canadian Institutes of Health Research (376560)
Topics: Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords: protease-activated receptors, G protein-coupled receptors, PAR1, PAR2, PAR4, proteolytic enzymes, biased signaling, receptor-effector interaction, receptor signaling mechanisms, structure-activity relationship, platelet function, inflammation
MeSH terms: Antineoplastic Agents, Humans, Peptide Hydrolases, Signal Transduction, Receptors, Thrombin, Receptors, G-Protein-Coupled, Receptors, Proteinase-Activated, Receptor, PAR-1, Receptor, PAR-2

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Molecular mechanisms regulating Proteinase-Activated Receptors (PARs)

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