Pharmacological agents selectively acting on the channel moieties of TRPM6 and TRPM7. (September 2022)

• Record Type: Journal Article
• Authors: Rössig, Anna; Hill, Kerstin; Nörenberg, Wolfgang; Weidenbach, Sebastian; Zierler, Susanna; Schaefer, Michael; Gudermann, Thomas; Chubanov, Vladimir
• Is Part Of: Cell calcium. Volume 106(2022)
• Publication Date: 2022-09
• Subjects: TRP channels -- TRPM6 -- TRPM7 -- NS8593 -- iloperidone -- ifenprodil -- VER155008; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2022.102640
• Languages: English
• ISSNs: 0143-4160

Abstract

Highlights: Channel-kinases TRPM6 and TRPM7 control the organismal balance of divalent cations. Impaired functions of TRPM6 and TRPM7 affect normal prenatal development and healthy adulthood. Pharmacological agents are required for selective targeting of TRPM6 and TRPM7 in preclinical disease models. Iloperidone, ifenprodil, and VER155008 were identified as specific and potent inhibitors of the TRPM6 and TRPM7 channels. Abstract: The transient receptor potential cation channel, subfamily M, members 6 and 7 (TRPM6 and TRPM7) are homologous membrane proteins encompassing cation channel units fused to cytosolic serine/threonine-protein kinase domains. Clinical studies and experiments with animal disease models suggested that selective inhibition of TRPM6 and TRPM7 currents might be beneficial for subjects with immune and cardiovascular disorders, tumours and other pathologies, but the suitable pharmacological toolkit remains underdeveloped. The present study identified small synthetic molecules acting specifically on the channel moieties of TRPM6 and TRPM7. Using electrophysiological analysis in conjunction with Ca 2+ imaging, we show that iloperidone and ifenprodil inhibit the channel activity of recombinant TRPM6 with IC50 values of 0.73 and 3.33 µM, respectively, without an impact on the TRPM7 channel. We also found that VER155008 suppresses the TRPM7 channel with an IC50 value of 0.11 µM but does not affect TRPM6. Finally, the effects of iloperidone and VER155008 were found to be suitable for blocking native endogenous TRPM6 and TRPM7 in a collection of mouse and human cell models. Hence, the identification of iloperidone, ifenprodil, and VER155008 allows for the first time to selectively manipulate TRPM6 and TRPM7 currents. Graphical abstract: Image, graphical abstract