Arrhythmia's resulting from a disturbance of automaticity are a significant cause of brady- and tachy- arrhythmias and morbidity in-patients with heart disease. Limitations in pacemaker and pharmacologic treatment of these conditions are well known. Pharmacologic treatment of arrhythmia's will be improved through rational drug design targeted to specific proteins in which the identity, structure, and biophysics are known. The molecular basis of K+ channels that contribute to normal and abnormal automaticity remains elusive. In addition to the existence of multiple K+ channel types, significant differences in channel distribution in the atrium are suggested by the substantial regional differences in repolarization and response to external interventions. In this regard, different patterns of current expression have recently been demonstrated in human atria cells. This suggests that differential patterns of gene expression may exist in the atrium, which could have a profound influence on therapeutic strategies for atria arrhythmia's. Recent molecular studies have demonstrated that mutations of h-erg (human-erg-related gene) are responsible for a form of the familial long QT syndrome and might encode for IKr. However, a variety of discrepancies between the properties of the heterologously expressed h- erg and native IKr, leave the mechanistic link between defect and disease unresolved. The central hypotheses of this proposal is that Ikr is an essential component of the generation of normal and abnormal automaticity, that erg, likely in combination with other alpha and beta sub-units, forms the molecular basis of IKr, and that heterogeneous distribution of erg channels in the atrium may be functionally important. The applicant proposes to carry our a combined voltage-clamp study of IKr in isolated ferret atria and SA nodal myocytes and of an f-erg clone expressed in ocytes or mammalian cell lines.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL019216-21A1
Application #
2027997
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1976-05-01
Project End
2000-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
21
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Wang, Shimin; Bondarenko, Vladimir E; Qu, Yu-jie et al. (2005) Time- and voltage-dependent components of Kv4.3 inactivation. Biophys J 89:3026-41
Wang, Shimin; Morales, Michael J; Qu, Yu-Jie et al. (2003) Kv1.4 channel block by quinidine: evidence for a drug-induced allosteric effect. J Physiol 546:387-401
Bett, Glenna C L; Rasmusson, Randall L (2003) Functionally-distinct proton-binding in HERG suggests the presence of two binding sites. Cell Biochem Biophys 39:183-93
Strauss, Harold C; Rasmusson, Randall L (2002) Restitution, ventricular fibrillation, and drugs: where are we now? J Cardiovasc Electrophysiol 13:915-7
Patel, Sangita P; Campbell, Donald L; Strauss, Harold C (2002) Elucidating KChIP effects on Kv4.3 inactivation and recovery kinetics with a minimal KChIP2 isoform. J Physiol 545:5-11
Brahmajothi, M V; Campbell, D L; Rasmusson, R L et al. (1999) Distinct transient outward potassium current (Ito) phenotypes and distribution of fast-inactivating potassium channel alpha subunits in ferret left ventricular myocytes. J Gen Physiol 113:581-600
Rasmusson, R L; Wang, S; Castellino, R C et al. (1997) The beta subunit, Kv beta 1.2, acts as a rapid open channel blocker of NH2-terminal deleted Kv1.4 alpha-subunits. Adv Exp Med Biol 430:29-37
Wang, S; Morales, M J; Liu, S et al. (1997) Modulation of HERG affinity for E-4031 by [K+]o and C-type inactivation. FEBS Lett 417:43-7
Wang, S; Liu, S; Morales, M J et al. (1997) A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes. J Physiol 502 ( Pt 1):45-60
Liu, S; Rasmusson, R L (1997) Hodgkin-Huxley and partially coupled inactivation models yield different voltage dependence of block. Am J Physiol 272:H2013-22

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