ArticleAmerican journal of physiology. Cell physiology2008
Src tyrosine kinase alters gating of hyperpolarization-activated HCN4 pacemaker channel through Tyr531.
Article in American journal of physiology. Cell physiology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 45 citations in OpenAlex.
- Review: HCN Channels in the Heart.Current cardiology reviews · 2022Review
- Regulation of HCN Channels by Protein Interactions.Frontiers in physiology · 2022Review
- Contribution of HCN1 variant to sinus bradycardia: A case report.Journal of arrhythmia · 2021Article
- Plant Cyclic Nucleotide-Gated Channels: New Insights on Their Functions and Regulation.Plant physiology · 2020Article
- Isoform-specific regulation of HCN4 channels by a family of endoplasmic reticulum proteins.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- HCN4 knockdown in dorsal hippocampus promotes anxiety-like behavior in mice.Genes, brain, and behavior · 2019Article
- HCN Channels: New Therapeutic Targets for Pain Treatment.Molecules (Basel, Switzerland) · 2018Review
- Protein Kinase 2Journal of the American Society of Nephrology : JASN · 2018Article
- Crizotinib Inhibits Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 4 Activity.Cardio-oncology (London, England) · 2017Article
- Current understanding of the pathophysiological mechanisms responsible for inappropriate sinus tachycardia: role of the If "funny" current.Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing · 2016Review
- Serotonergic regulation of excitability of principal cells of the dorsal cochlear nucleus.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- HCN channels--modulators of cardiac and neuronal excitability.International journal of molecular sciences · 2015Review
- Article
- PP2 prevents β-adrenergic stimulation of cardiac pacemaker activity.Journal of cardiovascular pharmacology · 2014Article
- Up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) by specific interaction with K+ channel tetramerization domain-containing protein 3 (KCTD3).The Journal of biological chemistry · 2013Article
- Dual Regulation of Voltage-Sensitive Ion Channels by PIP(2).Frontiers in pharmacology · 2012Article
- Towards an integrated view of HCN channel role in epilepsy.Current opinion in neurobiology · 2011Review
- Rescue of a trafficking defective human pacemaker channel via a novel mechanism: roles of Src, Fyn, and Yes tyrosine kinases.The Journal of biological chemistry · 2009Article
- Associated changes in HCN2 and HCN4 transcripts and I(f) pacemaker current in myocytes.Biochimica et biophysica acta · 2009Article
- Age-dependent differences in the inhibition of HCN2 current in rat ventricular myocytes by the tyrosine kinase inhibitor erbstatin.Pflugers Archiv : European journal of physiology · 2009Article
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6 authors at 1 institution in 1 country.
Funding
Abstract
We recently discovered that the constitutively active Src tyrosine kinase can enhance hyperpolarization-activated, cyclic nucleotide-gated (HCN) 4 channel activity by binding to the channel protein. To investigate the mechanism of modulation by Src of HCN channels, we studied the effects of a selective inhibitor of Src tyrosine kinase, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), on HCN4 and its mutant channels expressed in HEK 293 cells by using a whole cell patch-clamp technique. We found that PP2 can inhibit HCN4 currents by negatively shifting the voltage dependence of channel activation, decreasing the whole cell channel conductance, and slowing activation and deactivation kinetics. Screening putative tyrosine residues subject to phosphorylation yielded two candidates: Tyr(531) and Tyr(554). Substituting HCN4-Tyr(531) with phenylalanine largely abolished the effects of PP2 on HCN4 channels. Replacing HCN4-Tyr(554) with phenylalanine did not abolish the effects of PP2 on voltage-dependent activation but did eliminate PP2-induced slowing of channel kinetics. The inhibitory effects of HCN channels associated with reduced Src tyrosine activity is confirmed in HL-1 cardiomyocytes. Finally, we found that PP2 can decrease the heart rate in a mouse model. These results demonstrate that Src tyrosine kinase enhances HCN4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. The tyrosine residue that mediates most of Src's actions on HCN4 channels is Tyr(531).
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