Transient Receptor Potential Vanilloid 4 Regulation of Adenosine Triphosphate Release by the Adenosine Triphosphate Transporter Vesicular Nucleotide Transporter, a Novel Therapeutic Target for Gastrointestinal Baroreception and Chronic Inflammation.

Abstract

BACKGROUND:

Transient receptor potential vanilloid 4 (TRPV4) is activated by stretch (mechanical), warm temperature, some epoxyeicosatrienoic acids, and lipopolysaccharide. TRPV4 is expressed throughout the gastrointestinal epithelia and its activation induces adenosine triphosphate (ATP) exocytosis that is involved in visceral hypersensitivity. As an ATP transporter, vesicular nucleotide transporter (VNUT) mediates ATP storage in secretory vesicles and ATP release via exocytosis upon stimulation.

SUMMARY:

TRPV4 is sensitized under inflammatory conditions by a variety of factors, including proteases and serotonin, whereas methylation-dependent silencing of TRPV4 expression is associated with various pathophysiological conditions. Gastrointestinal epithelia also release ATP in response to hypo-osmolality or acid through molecular mechanisms that remain unclear. These synergistically released ATP could be involved in visceral hypersensitivity. Low concentrations of the first generation bisphosphate, clodronate, were recently reported to inhibit VNUT activity and thus clodronate may be a safe and potent therapeutic option to treat visceral pain. Key Messages: This review focuses on: (1) ATP and TRPV4 activities in gastrointestinal epithelia; (2) factors that could modulate TRPV4 activity in gastrointestinal epithelia; and (3) the inhibition of VNUT as a potential novel therapeutic strategy for functional gastrointestinal disorders.

• Authors: Hiroshi Mihara, Ammar Boudaka, Makoto Tominaga, Toshiro Sugiyama
• Journal: Digestion (Digestion) Vol. 101 Issue 1 Pg. 6-11 ( 2020) ISSN: 1421-9867 [Electronic] Switzerland
• PMID: 31770754 (Publication Type: Journal Article, Review)
• Copyright: © 2019 The Author(s) Published by S. Karger AG, Basel.

Chemical References

• Analgesics
• Nucleotide Transport Proteins
• Receptors, Purinergic P2
• Slc17a9 protein, human
• Slc17a9 protein, mouse
• TRPV Cation Channels
• TRPV4 protein, human
• Trpv4 protein, mouse
• Clodronic Acid
• Adenosine Triphosphate

Topics

• Abdominal Pain (drug therapy, etiology)
• Adenosine Triphosphate (metabolism)
• Analgesics (pharmacology, therapeutic use)
• Animals
• Chronic Disease
• Clodronic Acid (pharmacology, therapeutic use)
• Gastrointestinal Tract (drug effects, metabolism, physiopathology)
• Humans
• Inflammation (metabolism, physiopathology)
• Mice
• Mucous Membrane (drug effects, metabolism, physiopathology)
• Nucleotide Transport Proteins (antagonists & inhibitors, metabolism)
• Pressoreceptors (drug effects, metabolism, physiopathology)
• Receptors, Purinergic P2 (drug effects, metabolism)
• TRPV Cation Channels (metabolism)