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Secreted effectors of the innate mucosal barrier
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Michael A. McGuckin, Andre J. Ouellette, Gary D. Wu
Enteroendocrine cells account for approximately 1% of intestinal epithelial cells with about 15 different subtypes that express various enteric hormones. Downstream of the Notch–Math1 pathway is the bHLH transcription factor Neurogenin 3, which is required for development of the enteroendocrine cell lineage. Downstream of Neurogenin 3, additional bHLH and homeodomain transcription factors have been shown to be important for the development of specific enteroendocrine subtypes. Another relatively infrequent differentiated epithelial cell type is tuft cells that have a unique morphology with long and thick microvilli projecting into the lumen. These cells share morphologic and functional features with taste-receptor cells that express the cation channel Trpm5 and play a role in type 2 immune responses initiated by protozoa and helminth parasite infections, where they are the source of IL-25.
Ion Channels of Reward Pathway in Drug Abuse
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Transient receptor potential (TRP) channels are a large family of non-selective cation channels. Besides traditional ligand-gated opening, mechanical force, chemical stress, and temperature also can lead to channel opening. Most TRP channels are permeable to Ca2+ with the exceptions of TRPM4 and TRPM5, which are only permeable to monovalent cations. The TRP superfamily contains six groups: TRPA (ankyrin), TRPC (canonical), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPV (vanilloid). TRP channels were first identified in Drosophila melanogaster, and studies have found around 30 channels in mammals belonging to this superfamily. The diverse activation mechanisms and expression of these channels make them involved in a wide range of activities of the central and peripheral nervous systems. However, the roles of these channels in drug abuse have only recently begun to be explored, with one of the most thoroughly studied families of TRP channels in drug abuse being the TRPV family. The TRPV family contains six mammalian members: TRPV1-6. TRPV1-4 are all heat-activated channels, which exhibit cation non-selectivity and modest Ca2+ permeability. TRPV5 and TRPV6 are the only highly Ca2+-selective channels in the TRP family, and both are regulated by [Ca2+]i. In contrast with other TRPVs, the temperature sensitivity of TRPV5 and TRPV6 is relatively low. TRPV1-4 are also sensitive to a broad array of endogenous and synthetic ligands. For example, TRPV1 is activated by capsaicin, heat (≥43°C), and many other chemicals, including an endocannabinoid, anandamide; the topical analgesic, camphor; piperine in black pepper; and allicin in garlic (Caterina et al. 1997; Zygmunt et al. 1999; Xu, Blair, and Clapham 2005; McNamara, Randall, and Gunthorpe 2005; Macpherson et al. 2005). Activation of TRPV1 leads to membrane depolarization, and TRPV1-mediated current can be facilitated by extracellular acidification (Xu, Blair, and Clapham 2005). A pH change to <6, ethanol, and nicotine also have similar effects on TRPV1 activity (Trevisani et al. 2002; Liu et al. 2004).
Tuft cells: an emerging therapeutic target for pancreatitis and pancreatic cancer?
Published in Expert Opinion on Therapeutic Targets, 2020
Yuning Yang, Ling Ding, Zhiyun Cao, Dongfeng Qu, Nathaniel Weygant
Tuft cells in the normal pancreas can be potentially identified by a variety of structural and functional markers. Structural markers include actin-related cross-linking proteins such as advillin and fibrin, tubulin network and ankyrin adaptor proteins, and doublecortin-like kinase 1 (DCLK1). Functional markers include secreted and receptor proteins such as taste receptors (e.g. TRPM5, α-Gustducin) and phospholipase enzymes (e.g. PLCG2) [9], with likely roles in sensing activities in the pancreatic ducts and signaling to the immune system and other cell types. During pancreatitis, acinar cells replace damaged TCs with new TCs which are programmed to secrete IL-25, a cytokine with a tumor-suppressing effect in a variety of cancers [1]. Moreover, several studies have shown that TCs also release acetylcholine to signal to surrounding cell types. These cholinergic TCs are selectively distributed in interlobular ducts in the middle of the pancreas and may play an important role in the immune processes of infection and cancer [10].
Dietary experience with glucose and fructose fosters heightened avidity for glucose-containing sugars independent of TRPM5 taste transduction in mice
Published in Nutritional Neuroscience, 2023
Verenice Ascencio Gutierrez, Aracely Simental Ramos, Shushanna Khayoyan, Lindsey A. Schier
These published and preliminary findings leave open two, not mutually exclusive, main possibilities. First, sugar exposure specifically affects a signal related to fructose, which permits rats and mice to discriminate it from other sugars. Second, sugar exposure affects a signal that is specifically engaged by glucose and other glucose-containing sugars. The purpose of the present study was to determine how sugar exposure changes the relative behavioral responsivity to glucose, fructose, and other sugars to further refine the search for sensor mechanism. In Experiment 1, naïve and sugar-exposed C57BL6/J mice underwent a series of brief access tests with varying concentrations and formulations of glucose and fructose to test the hypothesis that experience with glucose and fructose specifically alters responding to glucose and glucose-containing sugars. Sclafani et al [29] recently showed that while sweet taste receptors are not required to detect glucose even in naïve mice, the transient receptor potential channel 5 (TRPM5) is. TRPM5 is also implicated in polysaccharide preference, at least at low concentrations [42]. TRPM5 is expressed in Type II taste cells, downstream of T1R2+T1R3 and other G-protein coupled receptors, where it plays an important role in transducing the cellular signal [31]. An earlier study indicates that the sweet receptors per se are not required, but it is still unclear if the responsible sensory signal would engage downstream transduction components via an alternative receptor. This is of special interest because many of the candidate sugar transporters and/or metabolic sensors are highly expressed in Type II cells. Therefore, Experiment 2 assessed whether the acquired responsivity to glucose and/or other glucose-containing sugars requires a TRPM5-mediated signal in TRPM5 KO mice.
The downregulation of sweet taste receptor signaling in enteroendocrine L-cells mediates 3-deoxyglucosone-induced attenuation of high glucose-stimulated GLP-1 secretion
Published in Archives of Physiology and Biochemistry, 2018
Fei Wang, Xiudao Song, Liang Zhou, Guoqiang Liang, Fei Huang, Guorong Jiang, Lurong Zhang
We examined the effects of 3DG on downstream signaling molecule of STRs in STC-1 cells under 25 mM glucose level. the protein expression of TRPM5 was also detected in STC-1 cells via Western blotting. As shown in Figure 4(A), STC-1 cells incubating with 3DG (300 ng/ml) for 1 h induced a significant reduction in TRPM5 protein expression under 25 mM glucose concentration compared to control. In addition, 3DG (300 ng/ml) also decreased intracellular cAMP concentration induced by 25 mM glucose in STC-1 cells (Figure 4(B)).