Thrombin receptors

Protease-activated receptors, PAR-1, PAR-2, PAR-3, PAR-4 Thrombin receptors Thrombin-related receptors, Trypsin receptor... 

In some cases, receptor inactivation, e.g., of the V2 vasopressin receptor, is mediated by agonist-induced enzymatic cleavage of the GPCR. This nonendocytic proteolysis is promoted by a plasma membrane-associated metalloprotease. Proteinase-activated receptors (PARs) such as the thrombin receptor also follow a distinctly different pathway. PARs require the enzymatic cleavage of their N terminus, and the newly generated N terminus activates the receptor. Once... 

The thrombin receptor is unusual in that the receptor is activated by the enzymatic action of thrombin which cleaves the N-terminus of the receptor leaving the receptor constitutively active. 

The protease activated receptors PAR-1 to PARA, of which PAR-1 is the thrombin receptor and PAR-2 conceivably a Factor-VIIa receptor, are particularly interesting cases. The ligands for these receptors are part of the N-terminal extension of the receptor. The enzyme (for example, thrombin) will bind and cleave off most of this extracellular segment and thereby reveal a new,... 

Hartwig, J. H., Bokoch, G. M. etal. Thrombin receptor ligation and activated Rac uncap actin filament barbed ends through phosphoinositide synthesis in permeabilized human platelets. Cell 82 643-653,1995. 

The protease-activated receptors (PARs), a subclass of GPCRs that function in the coagulation cascade, suggest that a comprehensive survey of the GPCR portion of the proteome provides information about the structure and function of this receptor class. The PAR factor II (thrombin) receptor-like 2 (F2RL2) is inactive in the cascade until proteolytic cleavage of its extracellular amino terminus. A Phe240Ser variant that is located in the second intracellular loop, found at a frequency of approx. 8%, disrupts receptor activation by proteolysis. 

Griffin, C. T., Srinivasan, Y., Zheng, Y. W., Huang, W., and Coughlin, S. R. (2001) A role of thrombin receptor signaling in endothelial cells during embryonic development. Science. 293, 1666-1670. 

Himbacine (80) Alkaloid SCH 530348 (TRA) (81) Cardiovascular diseases (antiplatelet agent) Thrombin receptor antagonist Phase III (acute coronary syndromes) Schering-Plough 623-626... 

Clasby MC, Chackalamannil S, Czamiecki M, Doller D, Eagen K, Greenlee W, Kao G Lin Y, Tsai H, Xia Y, Ahn HS, Agans-Fantuzzi J, Boykow G Chintala M, Foster C, Smith-Torhan A, Alton K, Bryant M, Hsieh Y, Fan J, Palamanda J. (2007) Metabolism-based identification of a potent thrombin receptor antagonist. J Med Chem 50 129-138. 

Activation by thromboxane and thrombin receptors has been described for the G subfamily. The effector molecules are not known at present. 

Aplysillin A (527), with unknown double bond geometries was isolated from Aplysina fistularis and is a weak thrombin receptor antagonist [442]. 

A THEORETICAL MODEL OF THE HUMAN THROMBIN RECEPTOR (PAR-1), THE FIRST KNOWN PROTEASE-ACTIVATED G-PROTEIN-COUPLED RECEPTOR... 

Figure 1. Diagram of the human thrombin receptor, viewed edge-on, showing the sequence around the proteolytic cleavage site (LDPR-SFLLRN) in the long extracellular amino-terminus and the seven transmembrane domains (TM1-TM7).

Initially, we attempted to build a 3-D homology model of the transmembrane regions of the human thrombin receptor from the structure of IBRD, which is available from the Brookhaven Protein Database. Unfortunately, the suboptimal placement of several amino acid side chains resulted in severe deviations from structural standards for membrane-bound receptors with a seven-helix bundle topology (Figure 2). For example, carboxylate and ammonium groups on amino acid side chains at a mid-helix location were directed into the membrane, rather than toward the inside of the helix bundle, and the hydrophobic packing between some helices was either poor or nonexistent. 

Figure 3. Key hydrogen-bonding network between side chains of the GPCR-con-served amino acids Asn-120 (TM1), Asp-148 (TM2), and Asp-367 (TM7) for human thrombin receptor.

Figure 5. Amino acid sequence alignment of thrombin receptors and PAR-2s from different species along TM4, EC2, and TM5. (See caption to Figure 4 for more details.)...

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