Browsing by Author "Premont, Richard T."

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    Microbial nitrogen limitation in the mammalian large intestine
    (Springer Nature, 2018-12) Reese, Aspen T.; Pereira, Fátima C.; Schintlmeister, Arno; Berry, David; Wagner, Michael; Hale, Laura P.; Wu, Anchi; Jiang, Sharon; Durand, Heather K.; Zhou, Xiyou; Premont, Richard T.; Diehl, Anna Mae; O'Connell, Thomas M.; Alberts, Susan C.; Kartzinel, Tyler R.; Pringle, Robert M.; Dunn, Robert R.; Wright, Justin P.; David, Lawrence A.; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Resource limitation is a fundamental factor governing the composition and function of ecological communities. However, the role of resource supply in structuring the intestinal microbiome has not been established and represents a challenge for mammals that rely on microbial symbionts for digestion: too little supply might starve the microbiome while too much might starve the host. We present evidence that microbiota occupy a habitat that is limited in total nitrogen supply within the large intestines of 30 mammal species. Lowering dietary protein levels in mice reduced their faecal concentrations of bacteria. A gradient of stoichiometry along the length of the gut was consistent with the hypothesis that intestinal nitrogen limitation results from host absorption of dietary nutrients. Nitrogen availability is also likely to be shaped by host-microbe interactions: levels of host-secreted nitrogen were altered in germ-free mice and when bacterial loads were reduced via experimental antibiotic treatment. Single-cell spectrometry revealed that members of the phylum Bacteroidetes consumed nitrogen in the large intestine more readily than other commensal taxa did. Our findings support a model where nitrogen limitation arises from preferential host use of dietary nutrients. We speculate that this resource limitation could enable hosts to regulate microbial communities in the large intestine. Commensal microbiota may have adapted to nitrogen-limited settings, suggesting one reason why excess dietary protein has been associated with degraded gut-microbial ecosystems.
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    S-nitrosylation is required for β2AR desensitization and experimental asthma
    (Elsevier, 2022) Fonseca, Fabio V.; Raffay, Thomas M.; Xiao, Kunhong; McLaughlin, Precious J.; Qian, Zhaoxia; Grimmett, Zachary W.; Adachi, Naoko; Wang, Benlian; Hausladen, Alfred; Cobb, Brian A.; Zhang, Rongli; Hess, Douglas T.; Gaston, Benjamin; Lambert, Nevin A.; Reynolds, James D.; Premont, Richard T.; Stamler, Jonathan S.; Pediatrics, School of Medicine
    The β2-adrenergic receptor (β2AR), a prototypic G-protein-coupled receptor (GPCR), is a powerful driver of bronchorelaxation, but the effectiveness of β-agonist drugs in asthma is limited by desensitization and tachyphylaxis. We find that during activation, the β2AR is modified by S-nitrosylation, which is essential for both classic desensitization by PKA as well as desensitization of NO-based signaling that mediates bronchorelaxation. Strikingly, S-nitrosylation alone can drive β2AR internalization in the absence of traditional agonist. Mutant β2AR refractory to S-nitrosylation (Cys265Ser) exhibits reduced desensitization and internalization, thereby amplifying NO-based signaling, and mice with Cys265Ser mutation are resistant to bronchoconstriction, inflammation, and the development of asthma. S-nitrosylation is thus a central mechanism in β2AR signaling that may be operative widely among GPCRs and targeted for therapeutic gain.