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The Role of Platelet-Activating Factor in Endotoxin-Related Disease
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Taco W. Kuijpers, Tom van der Poll
In general, GPCR members are involved in a wide spectrum of functional responses ranging from hormonal adaptations to a balanced regulation of cardiovascular function, blood pressure, and electrolyte levels. The nature of the ligands for the various GPCR members are diverse: lipid mediators, proteins, or electrolytes (Table 1).
Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
Overall, VMATs are regulated by changes in transcription, mRNA splicing of exons, and posttranscriptional modifications such as phosphorylation. The inactivation of transport by VMATs is facilitated by heterotrimeric G proteins. These membrane-associated proteins, which are activated by GPCR, are made up of alpha, beta, and gamma subunits. Activated Gαq down-regulates VMAT2-mediated Ser transport in blood platelets and inhibits VMAT2 activity in the brain. The exact signaling pathway for G protein-mediated regulation of VMATs is not completely clear.
Drugs of Abuse and Addiction
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Shalini Mani, Chahat Kubba, Aarushi Singh
G protein-coupled receptors (GPCRs) are an extensive class of receptors, bound to G-proteins that are hetrotrimeric in nature (Beck-Sickinger and Böhme, 2009). It mediates a wide variety of cellular functions including the alteration in the levels of cAMP, which acts as secondary messengers, mobilization of intracellular calcium, modifying the release of neurotransmitter, and reorganization or alteration of cellular gene expression (Kiselyov et al., 2003; Betke et al., 2012). Various preclinical models have depicted a correlation between drug abuse and addiction with GPCRs. Repeated exposure to psychostimulants such as cocaine, nicotine, alcohol, etc. produces irreversible changes in the ability of GPCRs to modulate neurotransmitter release; such changes lead to an alteration in the behavioral responses by either promoting or constraining the stimulating effects of a range of addictive drugs (Navarro et al., 2013). Three well-known classes of GPCRs are known to mediate the effect of abused drugs on CNS most effectively. These include dopamine receptors (D1–D5), cannabinoid type 1 receptors (CB1), and group II metabotropic glutamate receptors (mGlus).
Evolution of phage display libraries for therapeutic antibody discovery
Published in mAbs, 2023
GPCR represents a class of seven transmembrane receptors. GPCRs have been recognized as successful drug targets as approximately one third of the US Food and Drug Administration (FDA)-approved drugs target GPCRs.159,160 However, due to high hydrophobicity, conformational flexibility, and limited accessibility of epitopes on the extracellular portion, GPCRs are challenging targets for antibodies. To date, there are only two FDA-approved antibodies drugs targeting GPCRs: mogamulizumab and erenumab, which target CC chemokine receptor 4 and calcitonin gene-related peptide receptor, respectively.161 Phage display offers a valuable antibody discovery platform for targeting challenging targets, including ion channels, transporters, and GPCRs.162 For example, one synthetic antibody phage display library was designed by mining the sequences of all known GPCR ligand interactions and incorporating the identified binding motifs into CDRH3. As a result, this GPCR-focused library successfully led to discovery of a panel of antagonistic antibodies targeting glucagon-like peptide-1 receptor with high affinity.15
Identification of novel genes by targeted exome sequencing in Retinoblastoma
Published in Ophthalmic Genetics, 2022
Shilpa Bisht, Bhavna Chawla, Amit Kumar, Viswanathan Vijayan, Manoj Kumar, Pradeep Sharma, Rima Dada
GPR151 encodes an orphan member of the class A rhodopsin-like family of G-protein-coupled receptors (GPCRs). A general feature of GPCR signaling is the agonist-induced conformational change in the receptor, leading to activation of the heterotrimeric G protein (41). The activated G protein then binds to and activates numerous downstream effector proteins, which generate secondary messengers that regulate a broad range of cellular and physiological processes (42). Role of GPR151 is not elucidated in RB tumors yet but implicated in breast cancer (mediated by RPS7 gene) (43) and prostate cancer (mediated by ENO2 gene) (44). GPCRs have recently emerged as key molecules playing essential role during the processes of angiogenesis, tumorigenesis, and metastasis and have important implication in breast cancer progression and thus, poor prognosis (45). Therefore, we predicted that g.374C>A nonsense mutation in the GPCR family member (GPR151) generates inactivated GPR151 protein which may affect the essential cellular processes leading to progression and metastasis of RB tumors. Further studies are required in this direction to decipher the direct role of GPR151 in RB pathogenesis.
Gαs and Gαq/11 protein coupling bias of two AVPR2 mutants (R68W and V162A) that cause nephrogenic diabetes insipidus
Published in Journal of Receptors and Signal Transduction, 2022
G protein coupled receptors (GPCR) are involved in many physiological functions through G-protein signaling. They govern signal transduction of hormones, metabolites, neurotransmitters, odorant molecules, and ions via their specific topology which consists of transmembrane, extra-, and intracellular domains. Since approximately 800 members of GPCRs are identified in the human genome, they are the largest superfamily of cell receptors [1]. GPCRs are capable of transmitting a variety of extracellular signals into the cell and then they make a response through the second messengers. Ligand binding to the GPCR triggers a conformational change of the receptor and activates the dissociation of G-protein subunits (α subunit dissociates from βγ subunits) which activates downstream mediators to transduce the signal [2]. There are four subtypes of the alpha subunit of G-protein, including Gαs, Gαi/o, Gαq/11, and Gα12/13 which are responsible for generating different responses via second messengers [2]. For example, while Gαs (which is a stimulatory Gα protein) activation causes the generation of cAMP and subsequent activation of protein kinase A (PKA), Gαi/o (which is an inhibitory Gα protein) activation inhibits cAMP production and PKA activity in the cell. Also, signaling through Gαq/11 activates phospholipase C-β (PLCβ) which in turn induces inositol 1,4,5-triphosphate (IP3) and Ca2+ mobilization [3].