Inhibition of the transient receptor potential cation channel TRPM2 by 2‐aminoethoxydiphenyl borate (2‐APB)

Abstract

Background and purpose: Transient receptor potential melastatin 2 (TRPM2) is a non‐selective Ca²⁺‐permeable cation channel and is known to be activated by adenosine 5′‐diphosphoribose (ADP‐ribose) and hydrogen peroxide. TRPM2 current responses are reported to be drastically potentiated by the combination of each of these ligands with heat. Furthermore, the combination of cyclic ADP‐ribose with heat also activates TRPM2. Although flufenamic acid, antifungal agents (miconazole and clotrimazole), and a phospholipase A₂ inhibitor (N‐(p‐amylcinnamoyl)anthranilic acid) inhibit TRPM2, their inhibition was either gradual or irreversible. Experimental approach: To facilitate future research on TRPM2, we screened several compounds to investigate their potential to activate or inhibit the TRPM2 channels using the patch‐clamp technique in HEK293 cells, transfected with human TRPM2. Key results: 2‐aminoethoxydiphenyl borate (2‐APB) exhibited a rapid and reversible inhibition of TRPM2 channels that had been activated by its ADP‐ribose or cADP‐ribose and heat in a dose‐dependent manner (IC₅₀ about 1 μM). 2‐APB also inhibited heat‐evoked insulin release from pancreatic islets, isolated from rats. Conclusions and implications: 2‐APB proved to be a powerful and effective tool for studying the function of TRPM2. British Journal of Pharmacology (2008) 153, 1324–1330; doi:10.1038/sj.bjp.0707675; published online 21 January 2008