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Published on: May 16, 2022
Valdecoxib blocks rat TRPV2 channels
Yannik Bluhm1, Rick Raudszus1, Anne Wagner1
1Rudolf Boehm Institute of Pharmacology and Toxicology, Medical Faculty, Leipzig University, Härtelstr. 16-18, 04107, Leipzig, Germany.
Abstract:
The transient receptor potential vanilloid 2 (TRPV2) channel is broadly expressed in a multitude of different tissues and is implicated in the pathology of several diseases, such as the progression of different cancer types. However, a lack of specific, potent and non-toxic TRPV2 activators and inhibitors complicate further studies to clarify the role of TRPV2. We here present valdecoxib as a novel inhibitor of heterologously expressed rat TRPV2 channels in HEK293 cells and native TRPV2 channels, endogenously expressed in the rat basophilic leukemia (RBL-2H3) cell line. Fluorometric assays reveal an IC50 of 9 μM and 11 μM for TRPV2 in HEK293 and RBL-2H3 cells, respectively. Closely related TRPV1, TRPV3 or TRPV4 channels are not blocked by valdecoxib. The inhibition is reversible and direct as confirmed by whole-cell and excised inside-out electrophysiological recordings. Other cyclooxygenase-2 inhibitors do not affect TRPV2 activity. Furthermore, we demonstrate that the combined application of 2-aminoethoxydiphenyl borate (2-APB) and probenecid at concentrations, which, on their own, elicit only small TRPV2 currents, act in a highly synergistic manner when applied simultaneously. Taken together, we here provide novel tools and chemical lead structures for further studying TRPV2 channel function in native tissues.
Insights
Valdecoxib effectively inhibits rat transient receptor potential vanilloid 2 (TRPV2) channels, offering a new tool for disease research. This discovery provides novel chemical lead structures for studying TRPV2 channel function in various tissues.
Area of Science:
- Ion channel research
- Molecular pharmacology
- Cellular biology
Background:
- Transient receptor potential vanilloid 2 (TRPV2) channels are involved in various diseases, including cancer.
- Specific and non-toxic TRPV2 modulators are lacking, hindering research into TRPV2's role.
Purpose of the Study:
- To identify novel inhibitors and activators for transient receptor potential vanilloid 2 (TRPV2) channels.
- To provide new chemical tools for investigating TRPV2 channel function in native tissues.
Main Methods:
- Valdecoxib was tested as a TRPV2 inhibitor in HEK293 and RBL-2H3 cell lines.
- Fluorometric assays and electrophysiological recordings (whole-cell, inside-out) were used.
- Synergistic effects of 2-aminoethoxydiphenyl borate (2-APB) and probenecid on TRPV2 were investigated.
Main Results:
- Valdecoxib inhibited rat TRPV2 channels with IC50 values of 9 μM (HEK293) and 11 μM (RBL-2H3).
- Valdecoxib showed specificity, not blocking related TRPV1, TRPV3, or TRPV4 channels.
- Inhibition by valdecoxib was confirmed as reversible and direct.
- 2-APB and probenecid exhibited synergistic activation of TRPV2 channels.
Conclusions:
- Valdecoxib is a novel, specific, and reversible inhibitor of rat TRPV2 channels.
- This study provides valuable chemical tools for advancing TRPV2 research.
- Synergistic activation of TRPV2 by 2-APB and probenecid offers new avenues for channel modulation studies.
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