MrgprC11 Expression and Function in Vagal Afferent Nerves in the Esophagus

Noxious stimulation-induced esophageal nociception plays a crucial role in generating esophageal pain and heartburn, but the underlying mechanism remains unclear. MrgprC11 is a recently discovered member belonging to Mas1-related G protein-coupled receptor (Mrgpr) family, which is selectively expressed in afferent DRG neurons and distinctively encodes somatic pain and itch sensations. Whether MrgprC11 is also functionally expressed in esophageal afferent neurons and mediates esophageal nociception has yet to be defined. We first compared MrgprC11 mRNA expressions in the esophagus, DRG, and vagal ganglia by RT-PCR. MrgprC11-positive nerve fiber distributions were revealed by confocal imaging in the whole-mount esophageal tissues using the MrgprC11 tdTomato mouse. We then addressed the MrgprC11 agonist BAM8-22 evoked functional responses in vagal afferent neurons by two-photon imaging using pirt-GCaMP6 mice and in esophageal vagal C-fibers by extra-cellular recording from wild-type and Mrgpr-cluster-/- mice. MrgprC11 mRNA expression was identified in the DRG and vagal ganglia, but not the esophagus. MrgprC11-positive nerve fibers were richly distributed in the wall of the esophagus. MrgprC11 agonist BAM8-22 elicited a significant increase in calcium influx in vagal afferent neurons. When applied to the esophageal vagal C-fiber nerve terminals in extra-cellular recordings, BAM8-22 evoked action potential discharges in the C-fibers only in wild-type but not Mrgpr-cluster-/- mice. Following activation, esophageal distension-induced action potential discharges were significantly enhanced in wild-type but not knockout animals. The present study demonstrated a functional role of MrgprC11 in mediating activation and sensitization of esophageal vagal afferent C-fibers, revealing a new mechanism and potential target for esophageal nociception.