TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons

Wang, Runping; Lu, Yongjun; Cicha, Michael Z.; Singh, Madhu V.; Benson, Christopher J.; Madden, Christopher J.; Chapleau, Mark W.; Abboud, François M.

doi:10.1172/jci.insight.122058

Cited by 9 publications

(5 citation statements)

References 86 publications

(117 reference statements)

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“…More recent findings have been made with nociceptive neurons isolated from DRGs, where the GPCR-mediated chloride conductance was attributed to the opening of TMEM16A/Ano1 chloride channels secondary to the release of intracellular calcium stored in the endoplasmic reticulum juxtaposed to the channel (30,53). In nodose neurons innervating the stomach, similar findings have been made with cholecystokinin-induced stimulation, except the chloride channel was found to be TMEM16B/Ano2 (90). Bradykinin was also found to activate a chloride conductance in airway jugular neurons; moreover, non-selective chloride channel blockers partially inhibited bradykinin-induced actionpotential discharge in jugular C-fiber terminals innervating the trachea (51) and can lead to the inhibition of cough (56).…”

Section: Figure 2 Whole Mount Tracheal Preparation Immunostained For Gfpsupporting

confidence: 54%

Molecular/Ionic Basis of Vagal Bronchopulmonary C-Fiber Activation by Inflammatory Mediators

Undem

Sun

2020

Physiology

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Stimulation of bronchopulmonary vagal afferent C fibers by inflammatory mediators can lead to coughing, chest tightness, and changes in breathing pattern, as well as reflex bronchoconstriction and secretions. These responses serve a defensive function in healthy lungs but likely contribute to many of the signs and symptoms of inflammatory airway diseases. A better understanding of the mechanisms underlying the activation of bronchopulmonary C-fiber terminals may lead to novel therapeutics that would work in an additive or synergic manner with existing anti-inflammatory strategies.

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Section: Figure 2 Whole Mount Tracheal Preparation Immunostained For Gfpsupporting

confidence: 54%

Molecular/Ionic Basis of Vagal Bronchopulmonary C-Fiber Activation by Inflammatory Mediators

Undem

Sun

2020

Physiology

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“…Reduced expression of TMEM16B in the heterozygote knock-out of the channel in sensory neurons results in obese rats with loss of CCK sensitivity in intestinal nodose neurons, loss of CCK-induced satiety, and decreased energy expenditure. Our findings reveal that Ano2/TMEM16B expressed in sensory neurons selectively promotes a reflex increase in sympathetic nerve activity to brown adipose tissue and corresponding thermogenesis [24].…”

Section: Fourth Evolving Concept: the Regulation Of Intestinal Vagal Afferents And Their Microbiome Interactionsmentioning

confidence: 67%

“…The satiety effects and metabolic actions of cholecystokinin (CCK) have been viewed as potential therapeutic targets for obesity. We identified a Ca 2+ -activated chloride (Cl -) current (CaCC) that is evoked by CCK in intestinal vagal afferents of nodose neurons [24]. The CaCC subunit Anoctamin 2 (Ano2/TMEM16B) is the dominant contributor to this current.…”

Section: Fourth Evolving Concept: the Regulation Of Intestinal Vagal Afferents And Their Microbiome Interactionsmentioning

confidence: 99%

Four evolving concepts in molecular and clinical autonomic research

Abboud

2021

Clin Auton Res

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In reflecting on decades of autonomic research, I recall the 2009 Walter B. Cannon Memorial Award Lecture, which I entitled In Search of Autonomic Balance: The Good, The Bad and The Ugly [1]. The Good was the inhibition of excessive sympathetic nerve activity by baroreceptors and by cardiac and respiratory vagal afferents. The Bad was the loss of these inhibitory signals. The Ugly was the fact that the loss of the inhibitory signals enhances the excitatory signals (e.g., from chemoreceptors and somatic afferents). The discovery of the molecular determinants of afferent mechanical and chemical signaling, their paracrine activation, and their genetic regulation have revealed new mechanisms of cardiovascular autonomic dysfunction with potential therapeutic interventions. Namely, sophisticated optogenetic techniques allow activation of specific afferent autonomic nerves [16]; and novel surgical devices and approaches are used in clinical trials involving carotid sinus, glossopharyngeal, or vagus nerve stimulation, renal denervation, carotid body resection, and cardiac neuroablation.In this invited commentary commemorating the 30th anniversary of Clinical Autonomic Research, I will highlight progress in clinical autonomic research by briefly reviewing four evolving concepts in the field. I ask for your indulgence, as I focus on experimental themes specifically pursued at the University of Iowa Cardiovascular Research Center. Consequently, other relevant autonomic concepts may not have been discussed here.

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“…Gene ANO2 has been suggested as playing a role in the pathophysiology of childhood obesity [49]. Studies [50] have revealed that ANO2 is a Ca 2+ −activated chloride channel in vagal afferents of nodose neurons and a major determinant of CCK-induced satiety, body weight control, and energy expenditure, making it a potential therapeutic target in obesity. TNFRSF1 genotypes have been identified as significantly associated with sTNFR1 plasma levels in obese women [51].…”

Section: Discussionmentioning

confidence: 99%

A tree‐based gene–environment interaction analysis with rare features

Liu

Zhang

Ma³

2022

Statistical Analysis

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Gene–environment (G‐E) interaction analysis plays a critical role in understanding and modeling complex diseases. Compared to main‐effect‐only analysis, it is more seriously challenged by higher dimensionality, weaker signals, and the unique “main effects, interactions” variable selection hierarchy. In joint G‐E interaction analysis under which a large number of G factors are analyzed in a single model, effort tailored to rare features (e.g., SNPs with low minor allele frequencies) has been limited. Existing investigations on rare features have been mostly focused on marginal analysis, where various data aggregation techniques have been developed, and hypothesis testings have been conducted to identify significant aggregated features. However, such techniques cannot be extended to joint G‐E interaction analysis. In this study, building on a very recent tree‐based data aggregation technique, which has been developed for main‐effect‐only analysis, we develop a new G‐E interaction analysis approach tailored to rare features. The adopted data aggregation technique allows for more efficient information borrowing from neighboring rare features. Similar to some existing state‐of‐the‐art ones, the proposed approach adopts penalization for variable selection, regularized estimation, and respect of the variable selection hierarchy. Simulation shows that it has more accurate identification of important interactions and main effects than several competing alternatives. In the analysis of NFBC1966 study, the proposed approach leads to findings different from the alternatives and with satisfactory prediction and stability performance.

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TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons

Cited by 9 publications

References 86 publications

Molecular/Ionic Basis of Vagal Bronchopulmonary C-Fiber Activation by Inflammatory Mediators

Molecular/Ionic Basis of Vagal Bronchopulmonary C-Fiber Activation by Inflammatory Mediators

Four evolving concepts in molecular and clinical autonomic research

A tree‐based gene–environment interaction analysis with rare features

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