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Mibefradil is a tetralol derivative originally developed as an antagonist of T-type voltage-gated calcium (Ca 2+ ) channels to treat hypertension when used at nanomolar dosage. More recently, its therapeutic application in hypertension has declined and has been instead repurposed as a treatment of cancer cell proliferation and solid tumor growth. Beyond its function as a Ca v  blocker, the micromolar concentration of mibefradil can stimulate a rise in [Ca 2+ ] cyt  although the mechanism is poorly known. The chanzyme TRPM7 (transient receptor potential melastanin 7), the release of intracellular Ca 2+  pools, and Ca 2+  influx by ORAI channels have been associated with the increase in [Ca 2+ ] cyt  triggered by mibefradil. This study aims to investigate the cellular targets and pathways associated with mibefradil’s effect on [Ca 2+ ] cyt . To address these questions, we monitored changes in [Ca 2+ ] cyt  in the specialized mouse epithelial cells (LS8 and ALC) and the widely used HEK-293 cells by stimulating these cells with mibefradil (0.1 μM to 100 μM). We show that mibefradil elicits an increase in [Ca 2+ ] cyt  at concentrations above 10 μM (IC 50  around 50 μM) and a fast Ca 2+  increase capacity at 100 μM. We found that inhibiting IP 3  receptors, depleting the ER-Ca 2+  stores, or blocking phospholipase C (PLC), significantly decreased the capacity of mibefradil to elevate [Ca 2+ ] cyt.  Moreover, the transient application of 100 μM mibefradil triggered Ca 2+  influx by store-operated Ca 2+  entry (SOCE) mediated by the ORAI channels. Our findings reveal that IP 3 R and PLC are potential new targets of mibefradil offering novel insights into the effects of this drug.   Supplementary Information  The online version contains supplementary material available at 10.1186/s43556-021-00037-0.

Mibefradil alters intracellular calcium concentration by activation of phospholipase C and IP3 receptor function