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9‐Phenanthrol Inhibits Calcium Oscillations in HL‐1 Mouse Cardiomyocytes

Transient Receptor Potential Melastatin 4 (TRPM4) is functionally expressed throughout the heart and has been implicated as a calcium‐activated nonselective cation channel that mediates membrane depolarization. The functional significance of TRPM4 in regards to Ca2+ signaling and its effects on cellular excitability and pacemaker function remains inconclusive. We show by Fura2 Ca‐imaging that pharmacological inhibition of TRPM4 in HL‐1 mouse cardiac myocytes by 9‐phenathrol (10 μM) decreases Ca2+ oscillations followed by an overall increase in [Ca2+]i. The latter occurs also in HL‐1 cells in Ca‐free solution and after depletion of sarcoplasmic reticulum Ca2+ with thapsigargin (10 μM). Furthermore, by whole‐cell voltage clamp we show that 9‐ phenanthrol reversibly inhibits TRP‐like membrane current; by fluorescence immunohistochemistry we demonstrate that HL‐1 cells display punctate surface labeling with TRPM4 antibody. We conclude that 9‐phenanthrol inhibits TRPM4 ion channels in HL‐1 cells, which in turn decreases Ca2+ oscillations followed by a compensatory increase in [Ca2+]i from an intracellular store other than the sarcoplasmic reticulum. We speculate that the most likely source is the mitochondrion.