Structure, Function, Pharmacology, and Therapeutic Potential of the G Protein, GÎ±/q,11

Kamato, Danielle; Thach, Lyna; Bernard, Rebekah; Chan, Vincent; Zheng, Wenhua; Kaur, Harveen; Brimble, Margaret A.; Osman, Narin; Little, Peter J.

doi:10.3389/fcvm.2015.00014

Cited by 62 publications

(51 citation statements)

References 93 publications

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“…The 5-HT 2 Rs signal through Gα q GPCR and activate protein lipase C (PLC) to generate DAG and inositol triphosphate (IP 3 ) [51]. Thus, antagonizing these receptors would result in a decrease in DAG (Fig.…”

Section: Discussionmentioning

confidence: 99%

Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists

Boroda

Niccum

Raje

et al. 2017

Biochemical Pharmacology

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Diacylglycerol kinase alpha (DGKα) catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). Recently, DGKα was identified as a therapeutic target in various cancers, as well as in immunotherapy. Application of small-molecule DGK inhibitors, R59022 and R59949, induces cancer cell death in vitro and in vivo. The pharmacokinetics of these compounds in mice, however, are poor. Thus, there is a need to discover additional DGK inhibitors not only to validate these enzymes as targets in oncology, but also to achieve a better understanding of their biology. In the present study, we investigate the activity of ritanserin, a compound structurally similar to R59022, against DGKα. Ritanserin, originally characterized as a serotonin (5-HT) receptor (5-HTR) antagonist, underwent clinical trials as a potential medicine for the treatment of schizophrenia and substance dependence. We document herein that ritanserin attenuates DGKα kinase activity while increasing the enzyme’s affinity for ATP in vitro. In addition, R59022 and ritanserin function as DGKα inhibitors in cultured cells and activate protein kinase C (PKC). While recognizing that ritanserin attenuates DGK activity, we also find that R59022 and R59949 are 5-HTR antagonists. In conclusion, ritanserin, R59022 and R59949 are combined pharmacological inhibitors of DGKα and 5-HTRs in vitro.

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Section: Discussionmentioning

confidence: 99%

Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists

Boroda

Niccum

Raje

et al. 2017

Biochemical Pharmacology

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“…Earlier studies targeting the G q pathway used either genetic approaches (12,16,17) or compounds that interact with GPCRs (15,18) or G q downstream signaling (19). A G q inhibitor isolated from Chromobacterium sp.…”

Section: Discussionmentioning

confidence: 99%

Targeted inhibition of G _q signaling induces airway relaxation in mouse models of asthma

et al. 2017

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Obstructive lung diseases are common causes of disability and death worldwide. A hallmark feature is aberrant activation of G q protein-dependent signaling cascades. Currently, drugs targeting single G protein (heterotrimeric guanine nucleotide-binding protein AQ4 )-coupled receptors (GPCRs) are used to reduce airway tone. However, therapeutic efficacy is often limited, because various GPCRs contribute to bronchoconstriction, and chronic exposure to receptoractivating medications results in desensitization. We therefore hypothesized that pharmacological G q inhibition could serve as a central mechanism to achieve efficient therapeutic bronchorelaxation. We found that the compound FR900359 (FR), a membrane-permeable inhibitor of G q , was effective in silencing G q signaling in murine and human airway smooth muscle cells. Moreover, FR both prevented bronchoconstrictor responses and triggered sustained airway relaxation in mouse, pig, and human airway tissue ex vivo. Inhalation of FR in healthy wild-type mice resulted in high local concentrations of the compound in the lungs and prevented airway constriction without acute effects on blood pressure and heart rate. FR administration also protected against airway hyperreactivity in murine models of allergen sensitization using ovalbumin and house dust mite as allergens. Our findings establish FR as a selective G q inhibitor when applied locally to the airways of mice in vivo and suggest that pharmacological blockade of G q proteins may be a useful therapeutic strategy to achieve bronchorelaxation in asthmatic lung disease.

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“…YM-254890 has been available in very restricted amounts from Yamanochi Pharmaceutical and used, for example, to deconvolute GPCR signalling 15 . However, the supply of the compound has ended 16 , and there is currently an urgent need to generate YM-254890 as a valuable tool for studying G q -mediated signalling.…”

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confidence: 99%

Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors

et al. 2016

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G proteins are key mediators of G protein-coupled receptor signalling, which facilitates a plethora of important physiological processes. The cyclic depsipeptides YM-254890 and FR900359 are the only known specific inhibitors of the Gq subfamily of G proteins; however, no synthetic route has been reported previously for these complex natural products and they are not easily isolated from natural sources. Here we report the first total synthesis of YM-254890 and FR900359, as well as of two known analogues, YM-385780 and YM-385781. The versatility of the synthetic approach also enabled the design and synthesis of ten analogues, which provided the first structure–activity relationship study for this class of compounds. Pharmacological characterization of all the compounds at Gq-, Gi- and Gs-mediated signalling provided succinct information on the structural requirements for inhibition, and demonstrated that both YM-254890 and FR900359 are highly potent inhibitors of Gq signalling, with FR900359 being the most potent. These natural products and their analogues represent unique tools for explorative studies of G protein inhibition.

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Structure, Function, Pharmacology, and Therapeutic Potential of the G Protein, GÎ±/q,11

Cited by 62 publications

References 93 publications

Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists

Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists

Targeted inhibition of G _q signaling induces airway relaxation in mouse models of asthma

Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors

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Structure, Function, Pharmacology, and Therapeutic Potential of the G Protein, GÎ±/q,11

Cited by 62 publications

References 93 publications

Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists

Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists

Targeted inhibition of G q signaling induces airway relaxation in mouse models of asthma

Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors

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Product

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Targeted inhibition of G _q signaling induces airway relaxation in mouse models of asthma