The overall goal of this project is to characterize the molecular mechanisms of HCN and hERG channel gating. HCN channels conduct the pacemaker current (If), and hERG channels conduct the rapid delayed rectifier current IKr. The voltage and time-dependent gating of these currents contribute to the rhythmic firing of cardiac pacemaker cells. HERG channels are opened by membrane depolarization, coupled to outward motion of the S4 voltage sensor. In contrast, HCN channels are opened by membrane hyperpolarization, coupled to inward motion of the S4 domain. We hypothesize that the opposite polarity of coupling between S4 movement and activation of HCN and hERG results from channel-specific interactions between residues in the S4-S5 linker and the C-terminal end of the S6 domain. For hERG, we have characterized the gating currents associated with S4 movement and the structural basis for drug binding; we will extend these studies to HCN channels. In addition, the molecular mechanisms of altered hERG channel gating induced by changes in external cations will be determined. Ionic and gating currents will be recorded using two microelectrode and cut-open Vaseline gap voltage clamp techniques of channels heterologously expressed in Xenopus oocytes. These studies promise to further our understanding of the biological oscillator that controls heart rhythm.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065299-07
Application #
7171926
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2000-09-30
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
7
Fiscal Year
2007
Total Cost
$318,945
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Abbruzzese, Jennifer; Sachse, Frank B; Tristani-Firouzi, Martin et al. (2010) Modification of hERG1 channel gating by Cd2+. J Gen Physiol 136:203-24
Du, Yi-mei; Zhang, Xiao-xian; Tu, Dan-na et al. (2010) Molecular determinants of Kv1.5 channel block by diphenyl phosphine oxide-1. J Mol Cell Cardiol 48:1111-20
Cheng, Lan; Sanguinetti, Michael C (2009) Niflumic acid alters gating of HCN2 pacemaker channels by interaction with the outer region of S4 voltage sensing domains. Mol Pharmacol 75:1210-21
Brown, Scott; Sonntag, David P; Sanguinetti, Michael C (2008) A highly conserved alanine in the S6 domain of the hERG1 K+ channel is required for normal gating. Cell Physiol Biochem 22:601-10
Decher, Niels; Gonzalez, Teresa; Streit, Anne Kathrin et al. (2008) Structural determinants of Kvbeta1.3-induced channel inactivation: a hairpin modulated by PIP2. EMBO J 27:3164-74
Restier, Lioara; Cheng, Lan; Sanguinetti, Michael C (2008) Mechanisms by which atrial fibrillation-associated mutations in the S1 domain of KCNQ1 slow deactivation of IKs channels. J Physiol 586:4179-91
Piper, David R; Rupp, Jason; Sachse, Frank B et al. (2008) Cooperative interactions between R531 and acidic residues in the voltage sensing module of hERG1 channels. Cell Physiol Biochem 21:37-46
Rosati, Barbara; Dong, Min; Cheng, Lan et al. (2008) Evolution of ventricular myocyte electrophysiology. Physiol Genomics 35:262-72
Cheng, Lan; Kinard, Krista; Rajamani, Ramkumar et al. (2007) Molecular mapping of the binding site for a blocker of hyperpolarization-activated, cyclic nucleotide-modulated pacemaker channels. J Pharmacol Exp Ther 322:931-9
Fernandez, David; Ghanta, Azad; Kinard, Krista I et al. (2005) Molecular mapping of a site for Cd2+-induced modification of human ether-a-go-go-related gene (hERG) channel activation. J Physiol 567:737-55

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