TRPV3 endogenously expressed in murine colonic epithelial cells is inhibited by the novel TRPV3 blocker 26E01

Bischof, Maria; Olthoff, Stefan; Glas, Carina; Thorn‐Seshold, Oliver; Schaefer, Michael; Hill, Kerstin

doi:10.1016/j.ceca.2020.102310

Cited by 10 publications

(11 citation statements)

References 37 publications

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“…TRPV3 is known to be activated by numerous stimuli, such as heat (22‐40°C) or various spices (eg thymol, menthol, carvacrol) 5,75,76 . The physiological function of TRPV3 is generally poorly understood 77 and research is hampered by the lack of commercially available specific agonists or blockers although the race for the development of such agents is on 50 . TRPV3 is highly expressed by the keratinocytes of the skin, where gain of function mutations are linked to a hereditary hyperkeratosis that can be so severe that joints are immobilized 78 .…”

Section: Discussionmentioning

confidence: 99%

“…49 GSK1016790A is currently thought to be selective for TRPV4. Unfortunately, there are currently no commercially available specific agonists or antagonists for TRPV3, 50 but if TRPV3 is functionally expressed, it should be activated by 2-APB. 2-APB is a classical TRP channel agonist that activates TRPV3, but also TRPV1, TRPV2 and TRPA1, but not TRPV4, TRPV5 or TRPV6, 51,52 with inhibitory effects on TRPC4, TRPC5, TRPC6, TRPM8 and TRPP1.…”

Section: Discussionmentioning

confidence: 99%

“…5,75,76 The physiological function of TRPV3 is generally poorly understood 77 and research is hampered by the lack of commercially available specific agonists or blockers although the race for the development of such agents is on. 50 TRPV3 is highly expressed by the keratinocytes of the skin, where gain of function mutations are linked to a hereditary hyperkeratosis that can be so severe that joints are immobilized. 78 Very little information is available for the role of TRPV3 in the gastrointestinal tract.…”

Section: Discussionmentioning

confidence: 99%

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TRPV3 and TRPV4 as candidate proteins for intestinal ammonium absorption

Manneck

Braun²,

Schrapers³

et al. 2021

Acta Physiologica

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Aim Absorption of ammonia from the gut has consequences that range from encephalitis in hepatic disease to global climate change induced by nitrogenous excretions from livestock. Since patch clamp data show that certain members of the transient receptor potential (TRP) family are permeable to NH4+, participation in ammonium efflux was investigated. Methods Digesta, mucosa and muscular samples from stomach, duodenum, jejunum, ileum, caecum and colon of pigs were analysed via colourimetry, qPCR, Western blot, immunohistochemistry and Ussing chambers. Results qPCR data show high duodenal expression of TRPV6. TRPM6 was highest in jejunum and colon, with expression of TRPM7 ubiquitous. TRPM8 and TRPV1 were below detection. TRPV2 was highest in the jejunum but almost non‐detectable in the colon. TRPV4 was ubiquitously expressed by mucosal and muscular layers. TRPV3 mRNA was only found in the mucosa of the caecum and colon, organs in which NH4+ was highest (>7 mmol·L−1). Immunohistochemically, an apical expression of TRPV3 and TRPV4 could be detected in all tissues, with effects of 2‐APB and GSK106790A supporting functional expression. In symmetrical NaCl Ringer, removal of mucosal Ca2+ and Mg2+ increased colonic short circuit current (Isc) and conductance (Gt) by 0.18 ± 0.06 µeq·cm−2·h−1 and 4.70 ± 0.85 mS·cm−2 (P < .05, N/n = 4/17). Application of mucosal NH4Cl led to dose‐dependent and divalent‐sensitive increases in Gt and Isc, with effects highest in the caecum and colon. Conclusion We propose that TRP channels contribute to the intestinal transport of ammonium, with TRPV3 and TRPV4 promising candidate proteins. Pharmacological regulation may be possible.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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TRPV3 and TRPV4 as candidate proteins for intestinal ammonium absorption

Manneck

Braun²,

Schrapers³

et al. 2021

Acta Physiologica

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“…TRPV3 is expressed by the apical membrane of colonocytes not only in rats and humans [ 50 ], but also in the pig (Manneck et al, submitted). Because commercially available specific agonists or inhibitors of TRPV3 are still in the process of being developed [ 51 ], we compared the responses of thymol (which strongly activates TRPV3 [ 25 , 41 ]) to those to cinnamaldehyde using Ussing chamber experiments on native epithelia and patch clamp experiments with overexpressing cells.…”

Section: Discussionmentioning

confidence: 99%

The TRPA1 Agonist Cinnamaldehyde Induces the Secretion of HCO3− by the Porcine Colon

Manneck

Manz

Braun³

et al. 2021

IJMS

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A therapeutic potential of the TRPA1 channel agonist cinnamaldehyde for use in inflammatory bowel disease is emerging, but the mechanisms are unclear. Semi-quantitative qPCR of various parts of the porcine gastrointestinal tract showed that mRNA for TRPA1 was highest in the colonic mucosa. In Ussing chambers, 1 mmol·l−1 cinnamaldehyde induced increases in short circuit current (ΔIsc) and conductance (ΔGt) across the colon that were higher than those across the jejunum or after 1 mmol·l−1 thymol. Lidocaine, amiloride or bumetanide did not change the response. The application of 1 mmol·l−1 quinidine or the bilateral replacement of 120 Na+, 120 Cl− or 25 HCO3− reduced ΔGt, while the removal of Ca2+ enhanced ΔGt with ΔIsc numerically higher. ΔIsc decreased after 0.5 NPPB, 0.01 indometacin and the bilateral replacement of 120 Na+ or 25 HCO3−. The removal of 120 Cl− had no effect. Cinnamaldehyde also activates TRPV3, but comparative measurements involving patch clamp experiments on overexpressing cells demonstrated that much higher concentrations are required. We suggest that cinnamaldehyde stimulates the secretion of HCO3− via apical CFTR and basolateral Na+-HCO3− cotransport, preventing acidosis and damage to the epithelium and the colonic microbiome. Signaling may involve the opening of TRPA1, depolarization of the epithelium and a rise in PGE2 following a lower uptake of prostaglandins via OATP2A1.

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“…The therapeutic potential of TRPV3 inhibitors in itch and pain is also recently reported by two independent laboratories 28 , 29 . However, all of these inhibitors are either nonselective or less potent 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , and it is imperative to identify selective and potent TRPV3 inhibitors that can be used either to further understand the channel pharmacology or lead to development potential for novel therapy of dermatitis and chronic pruritus.…”

Section: Introductionmentioning

confidence: 99%