The Role of Thrombin and Thrombin Receptors in the Brain

Luo, Weibo; Wang, Yingfei; Reiser, Georg

doi:10.1007/978-0-387-09637-7_8

Cited by 6 publications

(17 citation statements)

References 165 publications

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“…GPCRs, like proteinase‐activated receptors (PARs), nucleotide P2Y receptors, and opioid receptors, exert important biological functions in the brain. PARs are widely expressed in the brain and regulate brain development, neuronal death and survival, cell proliferation, and inflammation in response to extracellular serine proteases, like thrombin, trypsin, and tryptase (Luo et al. 2007a, 2008).…”

mentioning

confidence: 99%

Proteinase‐activated receptors, nucleotide P2Y receptors, and μ‐opioid receptor‐1B are under the control of the type I transmembrane proteins p23 and p24A in post‐Golgi trafficking

Luo

Wang

Reiser

2011

Journal of Neurochemistry

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J. Neurochem. (2011) 117, 71–81. Abstract We recently characterized the proteinase‐activated receptor (PAR)‐2, a G protein‐coupled receptor (GPCR), as the first cargo protein recognized by p24A. Here, we demonstrate that p24A binds to several other GPCRs, including PAR‐1, the nucleotide receptors P2Y1, P2Y2, P2Y4, and P2Y11, as well as the μ‐opioid receptor 1B. The acidic amino acid residues Glu and Asp at the second extracellular loop of GPCRs are essential for interaction with p24A. p23, another member of the p24 family, also interacts with GPCRs, similar to p24A. However, p23 shows a delayed dissociation from PAR‐2 after activation of PAR‐2, compared to the dissociation between PAR‐2 and p24A. p24A and p23 arrest both P2Y4 receptor and μ‐opioid receptor 1B at the intracellular compartments, as observed for PAR‐2. A comparable result was obtained when we studied primary rat astrocytes in culture. Over‐expression of the N‐terminal p24A fragment impairs PAR‐2 resensitization in astrocytes that extends our findings to a native system. In summary, we demonstrate that p24A and p23 are specific cargo receptors of GPCRs and differentially control GPCR trafficking in the biosynthetic pathway, and thereby, p24A and p23 regulate GPCR signaling in astrocytes.

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confidence: 99%

Proteinase‐activated receptors, nucleotide P2Y receptors, and μ‐opioid receptor‐1B are under the control of the type I transmembrane proteins p23 and p24A in post‐Golgi trafficking

Luo

Wang

Reiser

2011

Journal of Neurochemistry

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“…PAR1 is also expressed in neurons and astrocytes in the central nervous system (CNS), and in neurons of the peripheral nervous system, where they have important regulatory roles both in normal and disease states [5,6,13,14]. In normal brain, thrombin is involved in the synaptic organization and plasticity, while in neurodegenerative disorders it has dual opposite effects [24,25]. Thus, low concentrations of thrombin rescue neural cells from death after brain damage, whereas at high concentrations augments the brain damage.…”

Section: Primary Structure Species and Cellular Specific Expressionmentioning

confidence: 99%

“…The complex interactome of PAR1 and its wide cellular expression give an idea of the multiple physiological functions of this receptor and of the pathological implications of its dysfunctions, mainly in the cardiovascular [9,11,157,158], immune [7,159], and nervous [24,25,160,161] systems, inflammation [7,[162][163][164] and cancer [12,165,166], that are summarized in Table 2. Many of these pleiotropic actions are PAR1mediated in combination with PAR2 or PAR4.…”

Section: Par1 Therapeutic Implicationsmentioning

confidence: 99%

From Multiple PAR1 Receptor/Protein Interactions to their Multiple Therapeutic Implications

Gutiérrez-Rodríguez¹,

Herranz

2015

CTMC

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PAR1, member of the family of protease-activated receptors, is a GPCR whose activation requires a proteolytic cleavage at its extracellular N-terminus to unveil a tethered activating ligand. Although thrombin is the main activator of this receptor, diverse other proteases can also activate and disarm PAR1. Besides, tethered activating ligand-based peptides (PAR-APs) can also activate the receptor. PAR1 mainly signals via G proteins but, it can also signal using β-arrestin pathways and by transactivation of other receptors. This complex PAR1 interactome is completed with the receptor desensitization, trafficking, and degradation. PAR1 has shown species-, cellular-, and physiological or pathological state-dependent specificity. This review try to give an overview on the complex PAR1 interactome, its therapeutic impact upon the cardiovascular, immune and nervous systems, inflammation and cancer, as well as, on its modulation with agonists and antagonists.

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“…In addition to the key role of thrombin in the blood coagulation cascade [1], this serine protease regulates multiple effects on an increasing variety of cells, such as: platelets [2,3], endothelial and smooth muscle cells [2,4], neurons and astrocytes in the nervous system [2,[4][5][6][7], immune and inflammatory cells [8,9], osteoblasts [10], and tumor cells [11][12][13][14]. These cellular effects are mainly mediated by the activation of the protease-activated receptor PAR1 [15].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of new peptide-based ureas and thioureas as potential antagonists of the thrombin receptor PAR1

Ventosa-Andrés

Valdivielso

Pappos

et al. 2012

European Journal of Medicinal Chemistry

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By applying a diversity oriented synthesis strategy for the search of new antagonists of the thrombin receptor PAR1, a series of peptide-based ureas and thioureas, including analogues of the PAR1 reference antagonist RWJ-58259, has been designed and synthesized. The general synthetic scheme involves reduction of basic amino acid-derived amino nitriles by hydrogen transfer from hydrazine monohydrate in the presence of Raney Ni, followed by reaction with diverse isocyanates and isothiocyanates, and protecting group removal. All new compounds have been evaluated as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN. Some protected peptide-based ureas displayed significant antagonist activity.

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The Role of Thrombin and Thrombin Receptors in the Brain

Cited by 6 publications

References 165 publications

Proteinase‐activated receptors, nucleotide P2Y receptors, and μ‐opioid receptor‐1B are under the control of the type I transmembrane proteins p23 and p24A in post‐Golgi trafficking

Proteinase‐activated receptors, nucleotide P2Y receptors, and μ‐opioid receptor‐1B are under the control of the type I transmembrane proteins p23 and p24A in post‐Golgi trafficking

From Multiple PAR1 Receptor/Protein Interactions to their Multiple Therapeutic Implications

Design, synthesis and biological evaluation of new peptide-based ureas and thioureas as potential antagonists of the thrombin receptor PAR1

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