Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 Internalization

Alvarez-Arce, Alejandro; Lee-Rivera, Irene; López, Edith; Hernández‐Cruz, Arturo; López-Colomé, Ana Marı́a

doi:10.1155/2017/1908310

Cited by 7 publications

(4 citation statements)

References 48 publications

(56 reference statements)

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“…At very high concentrations, calpain-2 was also shown to cleave PAR2, and the authors suggested that this cleavage event inactivated PAR2 [26]. Recently, calpain-1 was shown to be induced by thrombin-activated PAR1, and subsequently regulated the internalization of PAR1 [85].…”

Section: Cleavage and Activation Of Pars And Signal Transductionmentioning

confidence: 99%

Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases

2019

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Inflammatory diseases have become increasingly prevalent with industrialization. To address this, numerous anti-inflammatory agents and molecular targets have been considered in clinical trials. Among molecular targets, protease-activated receptors (PARs) are abundantly recognized for their roles in the development of chronic inflammatory diseases. In particular, several inflammatory effects are directly mediated by the sensing of proteolytic activity by PARs. PARs belong to the seven transmembrane domain G protein-coupled receptor family, but are unique in their lack of physiologically soluble ligands. In contrast with classical receptors, PARs are activated by N-terminal proteolytic cleavage. Upon removal of specific N-terminal peptides, the resulting N-termini serve as tethered activation ligands that interact with the extracellular loop 2 domain and initiate receptor signaling. In the classical pathway, activated receptors mediate signaling by recruiting G proteins. However, activation of PARs alternatively lead to the transactivation of and signaling through receptors such as co-localized PARs, ion channels, and toll-like receptors. In this review we consider PARs and their modulators as potential therapeutic agents, and summarize the current understanding of PAR functions from clinical and in vitro studies of PAR-related inflammation.

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Section: Cleavage and Activation Of Pars And Signal Transductionmentioning

confidence: 99%

Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases

2019

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“…On the other hand, biased PAR1 activation by aPC via a cleavage downstream of the canonical site (R 41 S 42 FLLR 46 //N 47 ) induce opposite effects than thrombin, such as anti-inflammatory effect and endothelial barrier protection [129,130]. PAR1 can also be activated in a biased manner by other proteinases such as MMP-13 [131], plasmin [89], KLKs [106,132], neutrophil elastase [133], proteinase-3 [133], cathepsin-G [134,135], granzyme-A [92,93], and calpain-1 [97,136] through proteolytic cleavage at multiple noncanonical sites (Fig. 5).…”

Section: Proteolytic Cleavage As a Regulator Of Biased Signaling In Parsmentioning

confidence: 99%

Molecular mechanisms regulating Proteinase‐Activated Receptors (PARs)

Chandrabalan

Ramachandran

2021

The FEBS Journal

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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 signalling. 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 signalling 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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“…GPER also contributes to the activation of the phospholipase C (PLC) pathway in other cell types (44). The activation of PLC may lead to an increase in intracellular Ca 2+ and regulated clathrin-dependent endocytosis (45,46). In HepG2 cells, PLCgamma (PLCγ) was activated, and intracellular Ca 2+ release was detected after βE2 treatment.…”

Section: Discussionmentioning

confidence: 99%

17β-Estradiol Inhibits PCSK9-Mediated LDLR Degradation Through GPER/PLC Activation in HepG2 Cells

Gao

Zhang

et al. 2020

Front. Endocrinol.

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Plasma levels of PCSK9 are significantly higher in postmenopausal women. Pharmacologically increased estrogen levels have been shown to lower PCSK9 and LDL-C levels in animals and humans. The action of estrogen suggests that it has the ability to prevent PCSK9-mediated LDLR degradation in liver cells. However, little is known about how estrogen alters PCSK9-mediated LDLR degradation. Here, we report that 17β-estradiol (βE2) reduces PCSK9-mediated LDLR degradation by a mechanism that involves activation of the G protein-coupled estrogen receptor (GPER). In cultured HepG2 cells, βE2 prevented the internalization of PCSK9, which subsequently lead to PCSK9-mediated LDLR degradation. The altered LDLR levels also resulted in an increase in LDL uptake that was not observed in the absence of PCSK9. In addition, we showed that clathrin was rapidly increased in the presence of PCSK9, and this increase was blocked by βE2 incubation, suggesting rapid recruitment of clathrin in HepG2 cells. PLCγ activation and intracellular Ca 2+ release were both increased due to the rapid effect of estrogen. By using a GPER antagonist G15, we demonstrated that the GPER mediates the action of estrogen. Together, the data from this in vitro study demonstrate that estrogen can regulate LDLR levels mainly through GPER activation, which prevents PCSK9-dependent LDLR degradation in HepG2 cells.

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Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 Internalization

Cited by 7 publications

References 48 publications

Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases

Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases

Molecular mechanisms regulating Proteinase‐Activated Receptors (PARs)

17β-Estradiol Inhibits PCSK9-Mediated LDLR Degradation Through GPER/PLC Activation in HepG2 Cells

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