TRPV2 ion channels expressed in inhibitory motor neurons of gastric myenteric plexus contribute to gastric adaptive relaxation and gastric emptying in mice

Abstract

Gastric adaptive relaxation (GAR) is impaired in ~40% of functional dyspepsia (FD) patients, and nitric oxide (NO) released from inhibitory motor neurons plays an important role in this relaxation. Although the underlying molecular mechanism of GAR is poorly understood, transient receptor potential channel vanilloid 2 (TRPV2) mechano- and chemoreceptors are expressed in mouse intestinal inhibitory motor neurons and are involved in intestinal relaxation. The aim of this study was to evaluate the distribution of TRPV2 in inhibitory motor neurons throughout the mouse gastrointestinal tract and the contribution of TRPV2 to GAR. RT-PCR and immunohistochemical analyses were used to detect TRPV2 mRNA and protein, respectively. Intragastric pressure was determined with an isolated mouse stomach. Gastric emptying (GE) in vivo was determined using a test meal. TRPV2 mRNA was detected throughout the mouse gastrointestinal tract, and TRPV2 immunoreactivity was detected in 84.3% of neuronal nitric oxide synthase-expressing myenteric neurons in the stomach. GAR, which was expressed as the rate of decline of intragastric pressure in response to volume stimuli, was significantly enhanced by the TRPV2 activator probenecid, and the enhancement was inhibited by the TRPV2 inhibitor tranilast. GE was significantly accelerated by TRPV2 agonist applications, and the probenecid-induced enhancement was significantly inhibited by tranilast coapplication. Mechanosensitive TRPV2 was expressed in inhibitory motor neurons in the mouse stomach and contributed to GAR and GE. TRPV2 may be a promising target for FD patients with impaired GAR.

Uricosuric targets of tranilast

“…), inhibition of cation channels (Mihara et al. ), mast cell stabilization (Sastre et al. ), and modulation of tryptophan metabolism (Munn et al.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…TRPV2 functions as the Ca 2+ entry channel in these structures (Nagasawa and Kojima, 2012). TRPV2 mediates the gastric adaptive relaxation in the stomach (Mihara et al, 2013). It is required for the LPS-induced cytokine production in macrophages (Yamashiro et al, 2010).…”

“…In dissociated myenteric neurons, TRPV2-like currents were detected in association with increased intestinal motility. In the stomach of the mouse, approximately 84% of neuronal NOS-expressing myenteric neurons coexpressed TRPV2, and gastric emptying was accelerated by the TRPV2 activator probenecid (Mihara et al, 2013).…”

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…Activation of TRPV2 stimulates CGRP release from DRG sensory neurons, indicating a pronociceptive and proinflammatory role (Qin et al, 2008). More recently TRPV2 has also been implicated in nitric oxide production for the control of intestinal motility (Mihara et al, 2013).…”