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Cellular calcium uptake is a controlled physiological process mediated by multiple ion channels. The exposure of cells to either one of the protein kinase C (PKC) inhibitors, staurosporine (STS) or PKC412, can trigger Ca 2+  influx leading to cell death. The precise molecular mechanisms regulating these events remain elusive. In this study, we report that the PKC inhibitors induce a prolonged Ca 2+  import through hyperpolarization‐activated cyclic nucleotide‐gated channel 2 (HCN2) in lung carcinoma cells and in primary culture of cortical neurons, sufficient to trigger apoptosis‐inducing factor (AIF)‐mediated apoptosis. Downregulation of HCN2 prevented the drug‐induced Ca 2+  increase and subsequent apoptosis. Importantly, the PKC inhibitors did not cause Ca 2+  entry into HEK293 cells, which do not express the HCN channels. However, introduction of HCN2 sensitized them to STS/PKC412‐induced apoptosis. Mutagenesis of putative PKC phosphorylation sites within the C‐terminal domain of HCN2 revealed that dephosphorylation of Thr 549  was critical for the prolonged Ca 2+  entry required for AIF‐mediated apoptosis. Our findings demonstrate a novel role for the HCN2 channel by providing evidence that it can act as an upstream regulator of cell death triggered by PKC inhibitors.

Critical role for hyperpolarization‐activated cyclic nucleotide‐gated channel 2 in the AIF‐mediated apoptosis