Multiple types of voltage-gated K+ (Kv) channels with distinct time- and voltage-dependent properties and pharmacological sensitivities have been identified in the mammalian myocardium. This diversity has a physiological significance in that the various Kv channels play distinct roles in controlling action potential waveforms and refractoriness. Although considerable progress has been made in identifying the Kv channel pore-forming (?) subunits that encode diverse cardiac Kv channels, the functional roles of the Kv channel accessory subunits (minK/ MiRPs, Kv?, KChAP, KChIP, DPPX) are rather poorly understood. Studies in heterologous expression systems suggest that Kv accessory subunits can modulate the properties of a variety of Kv ? subunit encoded channels and that each type of Kv channel likely is modulated by multiple accessory subunits. Other recent studies suggest that cardiac Kv (and other) channels function as components of macromolecular protein complexes, comprising pore-forming and accessory subunits, as well as additional regulatory proteins that influence channel properties and mediate interactions with the actin cytoskeleton and the extracellular matrix. To define the physiological roles of the Kv?1, KChlP2 and DPP6 subunits, the studies proposed here will probe directly the functioning of these subunits in the generation of the native Kv channels, lto,f, Ito.s, IK,slow and Iss, in intact cardiac (mouse ventricular) myocytes. The expression levels or the properties of the accessory subunits will be manipulated in vivo and in vitro, and the functional consequences of these manipulations on the properties and cell surface expression of myocardial lto,f, Ito.s, IK,slow and Iss will be determined directly (and simultaneously). The proposed studies will reveal whether individual Kv channel types are regulated/modulated by multiple Kv accessory subunits. In addition, these studies will allow direct testing of the hypothesis that Kv accessory subunits are multifunctional, regulating/modulating the functioning of multiple types of (Kv a subunit encoded) cardiac Kv channels. We anticipate that these studies will provide fundamentally important new insights into the role of Kv channel accessory subunits in the dynamic regulation of cardiac Kv channel macromolecular complexes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034161-22
Application #
7765555
Study Section
Special Emphasis Panel (ZRG1-CVS-N (02))
Program Officer
Wang, Lan-Hsiang
Project Start
1986-04-01
Project End
2012-03-31
Budget Start
2010-02-01
Budget End
2012-03-31
Support Year
22
Fiscal Year
2010
Total Cost
$342,000
Indirect Cost
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Hueneke, Rocco; Adenwala, Adam; Mellor, Rebecca L et al. (2017) Early remodeling of repolarizing K+ currents in the ?MHC403/+ mouse model of familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 103:93-101
Burel, Sophie; Coyan, Fabien C; Lorenzini, Maxime et al. (2017) C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation. J Biol Chem 292:17431-17448
Zhu, Wandi; Voelker, Taylor L; Varga, Zoltan et al. (2017) Mechanisms of noncovalent ? subunit regulation of NaV channel gating. J Gen Physiol :
Khandekar, Aditi; Springer, Steven; Wang, Wei et al. (2016) Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents. Circ Res 119:1324-1338
Yang, Kai-Chien; Nerbonne, Jeanne M (2016) Mechanisms contributing to myocardial potassium channel diversity, regulation and remodeling. Trends Cardiovasc Med 26:209-18
Nerbonne, Jeanne M (2016) Molecular Basis of Functional Myocardial Potassium Channel Diversity. Card Electrophysiol Clin 8:257-73
Peyronnet, RĂ©mi; Nerbonne, Jeanne M; Kohl, Peter (2016) Cardiac Mechano-Gated Ion Channels and Arrhythmias. Circ Res 118:311-29
Yang, Kai-Chien; Yamada, Kathryn A; Patel, Akshar Y et al. (2014) Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support. Circulation 129:1009-21
Nerbonne, Jeanne M (2014) Mouse models of arrhythmogenic cardiovascular disease: challenges and opportunities. Curr Opin Pharmacol 15:107-14
Foeger, Nicholas C; Wang, Wei; Mellor, Rebecca L et al. (2013) Stabilization of Kv4 protein by the accessory K(+) channel interacting protein 2 (KChIP2) subunit is required for the generation of native myocardial fast transient outward K(+) currents. J Physiol 591:4149-66

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