ArticleThe EMBO journal2010
Critical role for hyperpolarization-activated cyclic nucleotide-gated channel 2 in the AIF-mediated apoptosis.
Article in The EMBO journal, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 38 citations in OpenAlex.
- HCN2 Promotes BGN Transcription via REST to Regulate Ferroptosis and Tumor Progression in Bladder Cancer.International journal of molecular sciences · 2026Article
- Localization of hyperpolarization-activated cyclic nucleotide-gated channels in the vertebrate retinas across species and their physiological roles.Frontiers in neuroanatomy · 2024Review
- Repurposing hyperpolarization-activated cyclic nucleotide-gated channels as a novel therapy for breast cancer.Clinical and translational medicine · 2021Article
- Using the Oxytosis/Ferroptosis Pathway to Understand and Treat Age-Associated Neurodegenerative Diseases.Cell chemical biology · 2020Review
- Evidence for Effective Inhibitory Actions on Hyperpolarization-Activated Cation Current Caused byMolecules (Basel, Switzerland) · 2019Article
- Age-Dependent Up-Regulation of HCN Channels in Spiral Ganglion Neurons Coincide With Hearing Loss in Mice.Frontiers in aging neuroscience · 2018Article
- Characterization of the Role of the Malate Dehydrogenases to Lung Tumor Cell Survival.Journal of Cancer · 2017Article
- Identification of methylated genes in salivary gland adenoid cystic carcinoma xenografts using global demethylation and methylation microarray screening.International journal of oncology · 2016Article
- Synergistic killing of human small cell lung cancer cells by the Bcl-2-inositol 1,4,5-trisphosphate receptor disruptor BIRD-2 and the BH3-mimetic ABT-263.Cell death & disease · 2015Article
- Metabolic epistasis among apoptosis-inducing factor and the mitochondrial import factor CHCHD4.Cell cycle (Georgetown, Tex.) · 2015Article
- Activation of a TRP-like channel and intracellular Ca2+ dynamics during phospholipase-C-mediated cell death.Journal of cell science · 2014Article
- Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death.Cell research · 2014Article
- Caspase-2 promotes cytoskeleton protein degradation during apoptotic cell death.Cell death & disease · 2013Article
- Various modes of cell death induced by DNA damage.Oncogene · 2013Review
- AIF and Scythe (Bat3) regulate phosphatidylserine exposure and macrophage clearance of cells undergoing Fas (APO-1)-mediated apoptosis.PloS one · 2012Article
- Survivin monomer plays an essential role in apoptosis regulation.The Journal of biological chemistry · 2011Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 Ca²(+) 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 Ca²(+) 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 Ca²(+) increase and subsequent apoptosis. Importantly, the PKC inhibitors did not cause Ca²(+) 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 Thr⁵⁴⁹ was critical for the prolonged Ca²(+) 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.