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Analyzing the GPCR Function of Polycystin-1
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Stephen C. Parnell, Robin L. Maser, Brenda S. Magenheimer, James P. Calvet
The predicted structures of PC1 and PC2 led to early suggestions that they form a membrane receptor-ion channel complex.13,14 Supporting evidence came from studies in which coexpression of PC1 and PC2 in transfected cells was shown to generate a Ca2+ signal16 and where ciliary PC1-PC2 mediated fluid-flow stimulated transient elevations in intracellular Ca2+ in a ryanodine receptor-dependent fashion.17 Such observations led to the concept that the polycystin complex responds to ligand-mediated18 or mechanosensory 17 stimuli to regulate channel activity and initiate signal transduction. Early work from our group was the first to describe the PC1 protein as an atypical GPCR.19,20 Expression of the C-terminal cytosolic tail of PC1 was shown to stimulate a number of signaling pathways in transfected cells, leading to the activation of promoter-reporters such as AP-1 and NFAT.20–23 A membrane-proximal region of the PC1 C-tail was found to contain a heterotrimeric G-protein binding and activation domain19 that initiates signaling by activating Gi/o, Gq/11 and G12/13.20 PC1 has been shown to activate Gi/o and release Gβγ subunits to modulate ion channel activity in neuronal cells.24 As such, while it appears that PC1-PC2 is a signaling-responsive Ca2+ channel, the biochemical and cellular mechanisms of the complex are not well understood.25–27
Coagulation Theory, Principles, and Concepts
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Thrombomodulin was the missing key in the protein C-inhibitory pathway. It was not until its discovery that the protein C-inhibitory pathway became kinetically feasible as an in-vivo inhibitory mechanism. Thrombin slowly activates protein C, but when it binds to thrombomodulin its specificity is changed and it rapidly activates protein C. When thrombin is bound to thrombomodulin, it is no longer capable of converting fibrinogen to fibrin; thus it loses its coagulant activity and participates only as a component of an anticoagulation pathway. Thrombomodulin is an integral membrane protein and is found in the membranes of a large number of different cell types. In coagulation, its presence in the vascular endothelium affects coagulation most significantly. The apoprotein has a molecular weight of about 60,300. The structure is characterized by a cytoplasmic C-terminal tail region, a transmembrane section, a glycopeptide-like region, followed by several epidermal growth factor-like regions, a hydrophobic region, and terminates in the N-terminal lectin-like region. In this respect, it is similar to a number of other membrane receptor proteins.
The Role of Procoagulant Activity in Fulminant Viral Hepatitis
Published in Gary A. Levy, Edward H. Cole, Procoagulant Activity in Health and Disease, 2019
Stephen W. Chung, Chao-Ying Li, Julian Leibowitz, Gary A. Levy
In general, interaction of a membrane receptor with its ligand results in the generation of second messengers, which ultimately leads to alteration in cell function either by changes in nuclear transcription or activation/inactivation of cellular enzymes by phosphorylation events. Although the cell-surface MHV receptor has been cloned and sequenced,72 the biochemical events leading to the expression of the prothrombinase after the binding of the virus to its receptor are unknown.
Unmasking allosteric-binding sites: novel targets for GPCR drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Verònica Casadó-Anguera, Vicent Casadó
Typically, only small molecules or peptides are considered as allosteric modulators of guest (orthosteric) ligands of a protein (conduit) (see section 7.1). However, a second protein can also be considered an allosteric modulator. Working with membrane receptor, cytosolic, extracellular or, mainly, transmembrane proteins could act as allosteric modulators of the guest ligands interacting with the binding sites of the receptor (the conduit protein). These are non-classical examples of allosterism, including the lateral (oligomeric) and cytosolic allostery defined by Kenakin [20,22] and developed in section 7. In protein oligomers (see section 6), the modulator can be the partner protomer itself (section 7.3) or a small molecule binding to the allosteric site (section 7.2) or to the orthosteric site (section 7.4) of the partner protomer. In the last two cases, the conduits are the two oligomeric proteins connecting both binding sites, allosteric–orthosteric in 7.2 or orthosteric–orthosteric in 7.4. However, the guest ligand could also bind to the allosteric site and be modulated by the other allosteric or orthosteric sites within the dimer. Then, the modulator can be the partner protomer itself but also a ligand binding to an allosteric or an orthosteric site of the partner protomer. In this case, the same ligand can act as an orthosteric ligand for one protomer and as an allosteric ligand for the partner protomer within the dimeric or oligomeric complex (see examples in section 7.4 not only of non-classical allosterism but also of non-classical and unexpected allosteric sites).
Current and emerging pharmacotherapy for chronic spontaneous Urticaria: a focus on non-biological therapeutics
Published in Expert Opinion on Pharmacotherapy, 2021
Kam Lun Hon, Joyce T. S. Li, Alexander K.C. Leung, Vivian W. Y. Lee
G protein-coupled receptors (GPCRs) are the largest group of membrane receptor proteins. GPCRs and their downstream signaling pathways are common targets of drug therapy. Mas-related G protein-coupled receptors (MRGPRs) are a family of GPCRs while Mas-related G protein-coupled receptor X2 (MRGPRX2) is a subfamily of MRGPRs [157]. MRGPRX2 is selectively expressed in mast cells, especially in skin mast cells [158,159]. Ligand binding to MRGPRX2 may trigger mast cell degranulation, production of lipid mediators, or generation of cytokines and chemokines [160]. Ligands of MRGPRX2 include certain drugs and endogenous peptides [160]. Some chronic inflammatory diseases, for example, atopic dermatitis, CSU, and rosacea, may be associated with increased expression of MRGPRX2 or enhanced downstream signalling [161]. It is observed that CSU patients express higher number and higher percentage of MRGPRX2 in skin mast cells than healthy subjects [162].
Elevated expressions of SHP2 and GAB2 correlated with VEGF in eutopic and ectopic endometrium of women with ovarian endometriosis
Published in Gynecological Endocrinology, 2020
Yizhou Huang, Tao Zhang, Liqing Chen, Minghua Yu, Qin Liu, Caiyun Zhou, Qile Tang, Linpo Zhou, Hong Zhan, Juanqing Li, Kaihong Xu, Jun Lin
Src-homology-2-domain-containing phosphatase 2 (SHP2), encoded by PTPN11, is a ubiquitously expressed non-receptor protein tyrosine phosphatase (PTP). SHP2 is required for normal development, regulating cell survival, proliferation, migration, and differentiation involved in various signaling pathways downstream of growth factor and cytokine receptors [7]. Activating mutations or dysregulation of SHP2 has been implicated in developmental diseases and multiple cancer types, including leukemia, breast and lung cancer and neuroblastoma [8]. The Grb2-associated binding protein 2 (GAB2) is a scaffolding adapter protein that links plasma membrane receptor signaling with several downstream signal effectors including SHP2 [9]. GAB2 participates in immune response, Alzheimer's disease and human tumorigenesis, particularly in breast cancer, leukemia and ovarian cancer [10–12]. The interaction between GAB2 and SHP2 has been proven to be important in several human malignancies [12–14]. However, the expression pattern and potential role of SHP2 and GAB2 in endometriosis have not been studied.