Mrgprs on vagal sensory neurons contribute to bronchoconstriction and airway hyper-responsiveness

Han, Liang; Limjunyawong, Nathachit; Ren, Feng; Li, Zhe; Hall, O.; Steele, Haley; Zhu, Yuyan; Wilson, Julie; Mitzner, Wayne; Kollárik, Marián; Undem, Bradley J.; Canning, Brendan J.; Dong, Xinzhong

doi:10.1038/s41593-018-0074-8

Cited by 48 publications

(48 citation statements)

References 23 publications

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“…We were unable to show Mrgprc11‐immunolabeling in the peripheral nerve terminals of the Mrgprc11 + colonic DRG neurons, but this is probably due to a low protein abundance at peripheral sites that is beyond the detection limit of the methods used. These findings are in line with another recent study by Han et al who demonstrated an involvement of Mrgprc11 in the airway sensory innervation but were also unable to visualize Mrgprc11‐immunoreactivity in peripheral nerve terminals in the airways . The results of our tracing studies, however, unambiguously indicate that both at the mRNA and protein level, Mrgprc11 is present in the somata of DRG neurons that innervate the colon.…”

Section: Discussionsupporting

confidence: 90%

“…A better characterization of these drivers will improve our understanding of how gut nociception is regulated and, more importantly, help to define new therapeutic targets for chronic abdominal pain disorders such as IBD and IBS. In recent years, the murine Mas‐related G protein‐coupled receptor Mrgprc11 has emerged as a novel mediator of nociception in the sensory innervation of the skin and lung, yet its involvement in the sensory innervation of other organs is currently still unexplored. In this study, we identified a novel function for Mrgprc11 in the gut nociceptive innervation and propose the receptor as a new player in visceral hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…Animals were held vertically for 2 minutes to prevent expulsion of the enema. The dosage of BAM(8‐22) in this study was inferred from previous studies using BAM(8‐22) for in vivo experiments …”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, its role is not limited to somatosensory neurons. Mrgprc11 is also expressed by vagal jugular sensory neurons innervating the murine airway epithelium, where receptor activation induces acute bronchoconstriction and results in airway hyperresponsiveness . The expression of Mrgprc11 in sensory neurons, together with its role in mediating protective and nocifensive responses in both the skin and airways, suggests that the receptor acts as a more widespread mediator of nociception in different organ systems.…”

Section: Introductionmentioning

confidence: 99%

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Mas‐related G protein‐coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?

Remoortel

Ceuleers

Arora

et al. 2019

Neurogastroenterology Motil

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Background Visceral hypersensitivity, an important cause of abdominal pain in disorders such as IBD and IBS, presents with a poorly understood pathophysiology and limited treatment options. Several members of the Mas‐related G protein‐coupled receptor family (Mrgprs) have become promising targets in pain research. The potential link between the murine Mrgpr C11 (Mrgprc11) and gut nociception is currently uninvestigated. Therefore, we explored the expression and functional role of Mrgprc11 in the gut nociceptive innervation. Methods Mrgprc11 expression was evaluated in DRG neurons innervating the mouse colon using in situ hybridization and immunohistochemistry. Visceromotor responses to colorectal distension (CRD) assessed the effect of the Mrgprc11 agonist, BAM(8‐22), on colonic pain sensitivity in healthy mice. Moreover, we determined pERK1/2‐immunoreactivity in the thoracolumbar spinal cord after noxious CRD. Finally, from a translational point of view, we looked for expression of the human counterpart of Mrgprc11, MRGPRX1, in human thoracolumbar DRGs. Key Results In situ hybridization and immunohistochemistry revealed Mrgprc11 expression in colonic DRG neurons. Intracolonic administration of BAM(8‐22) significantly increased colonic pain sensitivity in an Mrgprc11‐dependent manner, and led to a significantly increased degree of neuronal activation in the splanchnic spinal cord upon noxious stimulation. Furthermore, MRGPRX1 expression was also detected in human thoracolumbar DRG neurons. Conclusions & Inferences Our findings established a novel function for Mrgprc11 in the gut nociceptive innervation and propose the receptor as a new player in visceral hypersensitivity. Given the presence of MRGPRX1 in human DRG neurons, our study warrants future research on its therapeutic potential in abdominal pain disorders.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mas‐related G protein‐coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?

Remoortel

Ceuleers

Arora

et al. 2019

Neurogastroenterology Motil

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“…To address ginger constituent‐elicited neuronal actions in the gut, we performed extracellular single‐unit recording of action potential discharges in ex vivo gastroesophageal‐vagal preparation from wild‐type mouse. Furthermore, we developed a novel approach by using two‐photon neuron imaging technique to address the neuronal population response in ex vivo gastroesophageal‐vagal preparation from our newly established Pirt‐GCaMP6s transgenic mouse line . Functional multi‐neuron calcium imaging is a novel technique that can record activation simultaneously from about 150‐200 neuronal cell bodies at a single‐cell resolution when stimuli are applied to their intact nerve endings in the peripheral tissue/organs .…”

Section: Discussionmentioning

confidence: 99%

Effects of ginger constituent 6‐shogaol on gastroesophageal vagal afferent C‐fibers

Huang

Patil

et al. 2019

Neurogastroenterology Motil

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Background Ginger has been used as an herbal medicine worldwide to relieve nausea/vomiting and gastrointestinal discomfort, but the cellular and molecular mechanisms of its neuronal action remain unclear. The present study aimed to determine the effects of ginger constituent 6‐shogaol on gastroesophageal vagal nodose C‐fibers. Methods Extracellular single‐unit recording and two‐photon nodose neuron imaging were performed, respectively, in ex vivo gastroesophageal‐vagal preparations from wild type and Pirt‐GCaMP6 transgenic mice. The action potential discharge or calcium influx evoked by mechanical distension and chemical perfusions applied to the gastroesophageal vagal afferent nerve endings were recorded, respectively, at their intact neuronal cell soma in vagal nodose ganglia. The effects of 6‐shogaol on nodose C‐fiber neurons were then compared and determined. Key Results Gastroesophageal application of 6‐shogaol‐elicited intensive calcium influxes in nodose neurons and evoked robust action potential discharges in most studied nodose C‐fibers. Such activation effects were followed by a desensitized response to the second application of 6‐shogaol. However, action potential discharges evoked by esophageal mechanical distension, after 6‐shogaol perfusion, did not significantly change. Pretreatment with TRPA1 selective blocker HC‐030031 inhibited 6‐shogaol‐induced action potential discharges in gastric and esophageal nodose C‐fiber neurons, suggesting that TRPA1 played a role in mediating 6‐shogaol‐induced activation response. Conclusion and Inferences This study provides evidence that ginger constituent 6‐shogaol directly activates vagal afferent C‐fiber peripheral gastrointestinal endings. This activation leads to desensitization to subsequent application of 6‐shogaol but not subsequent esophageal mechanical distension. Further investigation is required to establish a possible contribution in its anti‐emetic effects.

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Neuro‐immune interactions and the role of Mas‐related G protein‐coupled receptors in the gastrointestinal tract

Remoortel

Lambeets

Timmermans

2022

The Anatomical Record

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Over the past decade, the research field dealing with the role of a new family of Rhodopsin A-like G protein-coupled receptors, that is, the family of Mas-related G protein-coupled receptors (Mrgprs) has expanded enormously. A plethora of recent studies have provided evidence that Mrgprs are key players in itch and pain, as well as in the initiation and modulation of inflammatory/allergic responses in the skin. Over the years, it has become clear that this role is not limited to the skin, but extends to other mucosal surfaces such as the respiratory tract and the gastrointestinal (GI) tract. In the GI tract, Mrgprs have emerged as novel interoceptive sensory pathways linked to health and disease, and are in close functional association with the gut's immune system. This review aims to provide an update of our current knowledge on the expression, distribution and function of members of this Mrgpr family in intrinsic and extrinsic neuro-immune pathways related to the GI system.

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Mrgprs on vagal sensory neurons contribute to bronchoconstriction and airway hyper-responsiveness

Cited by 48 publications

References 23 publications

Mas‐related G protein‐coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?

Mas‐related G protein‐coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?

Effects of ginger constituent 6‐shogaol on gastroesophageal vagal afferent C‐fibers

Neuro‐immune interactions and the role of Mas‐related G protein‐coupled receptors in the gastrointestinal tract

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