The long-term goal of this application is to reconstitute the cardiac pacemaker channels in vitro and apply the HCN pacemaker channel proteins to the gene therapy of arrhythmias. Based on recent advances in HCN cloning, mRNA distribution, functional expression of channels in different cell types, and regulation by beta subunit and tyrosine phosphorylation (TYR PHOS), this application attempts to assess the individual contribution of three cardiac HCN isoforms to the distinct properties of the pacemaker current i(f) and examine the mechanism and cellular function of tyrosine kinases related to pacemaker activity through i(f). Employing a combined electrophysiology (two-electrode voltage clamp, single-cell perforated patch clamp) and molecular biology (RNAi, mutagenesis, recombinant DNA) techniques, we will investigate 1) the effects of tyrosine kinase activation on i(f) and HCN channel properties; 2) the role of a nonreceptor tyrosine kinase, Src, in the modulation by both receptor/nonreceptor tyrosine kinases of pacemaker channels; 3) the molecular mechanism of how TYR PHOS differentially regulates three cardiac HCN isoforms; and 4) the contribution of each HCN isoform and TYR PHOS on HCN channels to the pacemaker activities in different heart regions (e.g., SA node and ventricle). Xenopus laevis oocytes, human embryonic kidney 293 (HEK293) cells, and rat neonatal ventricular myocytes will be used to provide a quick assessment on HCN modulation by TYR PHOS, a mammalian background for regulatory studies of HCN channels, and the physiological significance of the role HCN isoforms may play in the TYR PHOS of i(f) in vivo. Sinus node disease and atrial fibrillation are among the most common arrhythmias in patients. I(f) is an important contributor to the regulation of cardiac pacemaker activity. Understanding the modulation of HCN channels that encode i(f) should have significant diagnostic and therapeutic implications.
| Huang, Jianying; Lin, Yen-Chang; Hileman, Stan et al. (2015) PP2 prevents isoproterenol stimulation of cardiac pacemaker activity. J Cardiovasc Pharmacol 65:193-202 |
| Huang, Jianying; Lin, Yen-Chang; Hileman, Stan et al. (2014) PP2 prevents ?-adrenergic stimulation of cardiac pacemaker activity. J Cardiovasc Pharmacol 63:533-43 |
| Lin, Yen-Chang; Huang, Jianying; Kan, Hong et al. (2012) Defective calcium inactivation causes long QT in obese insulin-resistant rat. Am J Physiol Heart Circ Physiol 302:H1013-22 |
| Lin, Yen-Chang; Huang, Jianying; Zhang, Qi et al. (2010) Inactivation of L-type calcium channel modulated by HCN2 channel. Am J Physiol Cell Physiol 298:C1029-37 |
| Lin, Yen-Chang; Huang, Jianying; Kan, Hong et al. (2009) Rescue of a trafficking defective human pacemaker channel via a novel mechanism: roles of Src, Fyn, and Yes tyrosine kinases. J Biol Chem 284:30433-40 |
| Yu, Han-Gang (2009) Racing of the biological pacemaker. Recent Pat DNA Gene Seq 3:193-200 |
| Zhang, Qi; Huang, Aijie; Lin, Yen-Chang et al. (2009) Associated changes in HCN2 and HCN4 transcripts and I(f) pacemaker current in myocytes. Biochim Biophys Acta 1788:1138-47 |
| Huang, Jianying; Huang, Aijie; Zhang, Qi et al. (2008) Novel mechanism for suppression of hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by receptor-like tyrosine phosphatase-alpha. J Biol Chem 283:29912-9 |
| Li, Chen-Hong; Zhang, Qi; Teng, Bunyen et al. (2008) Src tyrosine kinase alters gating of hyperpolarization-activated HCN4 pacemaker channel through Tyr531. Am J Physiol Cell Physiol 294:C355-62 |
| Yu, Xiao; Chen, Xiao-Wei; Zhou, Peng et al. (2007) Calcium influx through If channels in rat ventricular myocytes. Am J Physiol Cell Physiol 292:C1147-55 |
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