This proposal focuses on elucidation of the molecular, pharmacological and regulatory properties of an important K+ channel which is believed to be an essential repolarizing current during the cardiac action potential. As such, this particular delayed rectifier K+ channel, IKs, represents an important target site for several new class III antiarrhythmic agents. The applicant proposes to test the hypothesis that alterations in the genetic message encoding this channel may be directly responsible for at least one type of potentially lethal idiosyncratic drug response to class III agents observed in a small percentage of otherwise healthy patients.
The specific aims of the proposal include: (1) to measure and compare the biophysical properties of native and recombinant forms of IKs to determine whether or not the minK gene encodes an ion channel protein or instead represents a regulator or cofactor of an unidentified protein responsible for IKs in native cardiac cells and heterologous expression systems, (2) to test the hypothesis that a single amino acid mutation in minK (A112G) recently discovered by the applicant to be a polymorphism of the human minK gene, changes the sensitivity of expressed minK channels to the class III antiarrhythmic drug, NE-10064, by identifiable changes in expressed channel structure, and (3) to investigate the expression of native and recombinant forms of IKs in wild type and genetically altered murine embryonic cells and stem cell derived cardiocytes to study the developmental regulation of functional minK channels in mammalian heart. This last specific aim will test the hypotheses that expression of functional minK channels in the developing heart is regulated by the beta-adrenergic signaling cascade, and that the presence of message for minK alone in early stage murine embryonic cells is insufficient to cause expression of functional minK channels. The results of these studies should provide the most detailed description to date of the molecular and genetic properties of IKs and its relevance to human cardiovascular pharmacology and disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044365-07
Application #
6030601
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1993-02-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pharmacology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Barro-Soria, Rene; Rebolledo, Santiago; Liin, Sara I et al. (2014) KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps. Nat Commun 5:3750
Xiao, Ling; Koopmann, Tamara T; Ördög, Balázs et al. (2013) Unique cardiac Purkinje fiber transient outward current ?-subunit composition: a potential molecular link to idiopathic ventricular fibrillation. Circ Res 112:1310-22
Yu, Haibo; Lin, Zhihong; Mattmann, Margrith E et al. (2013) Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels. Proc Natl Acad Sci U S A 110:8732-7
Wang, Mi; Kass, Robert S (2012) Stoichiometry of the slow I(ks) potassium channel in human embryonic stem cell-derived myocytes. Pediatr Cardiol 33:938-42
Osteen, Jeremiah D; Barro-Soria, Rene; Robey, Seth et al. (2012) Allosteric gating mechanism underlies the flexible gating of KCNQ1 potassium channels. Proc Natl Acad Sci U S A 109:7103-8
Chan, Priscilla J; Osteen, Jeremiah D; Xiong, Dazhi et al. (2012) Characterization of KCNQ1 atrial fibrillation mutations reveals distinct dependence on KCNE1. J Gen Physiol 139:135-44
Li, Yong; Chen, Lei; Kass, Robert S et al. (2012) The A-kinase anchoring protein Yotiao facilitates complex formation between adenylyl cyclase type 9 and the IKs potassium channel in heart. J Biol Chem 287:29815-24
Chen, Lei; Kass, Robert S (2011) A-kinase anchoring protein 9 and IKs channel regulation. J Cardiovasc Pharmacol 58:459-13
Wang, Kai; Terrenoire, Cecile; Sampson, Kevin J et al. (2011) Biophysical properties of slow potassium channels in human embryonic stem cell derived cardiomyocytes implicate subunit stoichiometry. J Physiol 589:6093-104
Sampson, Kevin J; Kass, Robert S (2010) Molecular mechanisms of adrenergic stimulation in the heart. Heart Rhythm 7:1151-3

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