Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 316; no. 3; pp. G338 - G349
• Main Authors: Balemans, D., Aguilera-Lizarraga, J., Florens, M. V., Jain, P., Denadai-Souza, A., Viola, M. F., Alpizar, Y. A., Van Der Merwe, S., Vanden Berghe, P., Talavera, K., Vanner, S., Wouters, M. M., Boeckxstaens, G. E.
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.03.2019
• Subjects: Adult; Animal models; Animals; Ankyrins; Biopsy; Calcium (intracellular); Calcium imaging; Capsaicin receptors; Cinnamaldehyde; Data processing; Dorsal root ganglia; Female; Histamine; Histamine - metabolism; Humans; Intestine; Irritable bowel syndrome; Male; Mice, Transgenic; Middle Aged; Mucosa; Pain; Pain perception; Patients; Potentiation; Rectum; Sensory neurons; Sensory Receptor Cells - metabolism; Signal Transduction - physiology; Therapeutic applications; Transient Receptor Potential Channels - metabolism; Transient receptor potential proteins; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; histamine 1 receptor; sensitization; TRP channels; visceral hypersensitivity
• ISSN: 0193-1857; 1522-1547; 1522-1547
• DOI: 10.1152/ajpgi.00116.2018

Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca 2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H 1 R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca 2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H 1 R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H 1 R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H 1 R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H 1 R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H 1 R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H 1 R antagonism in IBS.