Atrial fibrillation (AF) is the most common clinical arrhythmia affecting American population and is associated with a significant increase in morbidity and mortality, yet, treatment strategies have proven largely inadequate. We have employed molecular genetic and electrophysiological recordings to demonstrate the development of AF in a mouse model with null mutation of an L-type Ca channel (LTCC), Cav1.3 (alphalD), which we have shown to be highly expressed in the atria. In addition, we have unmasked a novel finding, that there is a functional crosstalk between Ca and the K channels, mainly a small conductance Ca-activated K channel (SK channel) via cytoskeletal protein, alpha-actinin2. We hypothesize that the functional crosstalk between SK channels and Ca channels occur via cytoskeletal proteins. In other words, the interacting partners may serve as bridges for the crosstalk between Ca and K channels. We further hypothesize that regional-specific sub-cellular localization of the different isoforms of LTCC's in the heart results from specific interaction of Ca channels with interacting proteins. We predict that the specific sub-cellular localization and protein-protein interactions are critical in the functional properties of the channels. Abnormalities in the functions of these ion channel proteins can result in alteration of atrial refractory period and the increase occurrences of AF. Our study will directly examine the molecular mechanisms of the functional coupling of Ca-activated K channels and Ca channels as well as differential isoform-specific subcellular localization of the Ca channels in human atria, identify the novel interacting proteins and the functional significance of the interactions. The study will have important implication in our understandings of the repolarization in atria and may provide insights into novel therapy for atrial arrhythmias, a common problem encountered in our patient population. Motivation for the proposal is extremely high since we have already obtained new evidence to show that these channels are critically important in atrial myocytes. These studies will substantially expand our understanding of the specific functions of individual Ca and K channels and how they may coordinate to mediate normal cardiac function in human.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085844-04
Application #
7769564
Study Section
Special Emphasis Panel (ZRG1-CVS-A (03))
Program Officer
Przywara, Dennis
Project Start
2007-04-15
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$380,000
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Gluck, Jessica M; Herren, Anthony W; Yechikov, Sergey et al. (2017) Biochemical and biomechanical properties of the pacemaking sinoatrial node extracellular matrix are distinct from contractile left ventricular matrix. PLoS One 12:e0185125
Sirish, Padmini; Ledford, Hannah A; Timofeyev, Valeriy et al. (2017) Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6. Circ Arrhythm Electrophysiol 10:
López, Javier E; Sharma, Janhavi; Avila, Jorge et al. (2017) Novel large-particle FACS purification of adult ventricular myocytes reveals accumulation of myosin and actin disproportionate to cell size and proteome in normal post-weaning development. J Mol Cell Cardiol 111:114-122
Zhang, Zheng; Ledford, Hannah A; Park, Seojin et al. (2017) Distinct subcellular mechanisms for the enhancement of the surface membrane expression of SK2 channel by its interacting proteins, ?-actinin2 and filamin A. J Physiol 595:2271-2284
Frederich, Bert J; Timofeyev, Valeriy; Thai, Phung N et al. (2017) Electrotaxis of cardiac progenitor cells, cardiac fibroblasts, and induced pluripotent stem cell-derived cardiac progenitor cells requires serum and is directed via PI3'K pathways. Heart Rhythm 14:1685-1692
Sirish, Padmini; Li, Ning; Timofeyev, Valeriy et al. (2016) Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation. Circ Arrhythm Electrophysiol 9:
Awasthi, Samir; Izu, Leighton T; Mao, Ziliang et al. (2016) Multimodal SHG-2PF Imaging of Microdomain Ca2+-Contraction Coupling in Live Cardiac Myocytes. Circ Res 118:e19-28
Yechikov, Sergey; Copaciu, Raul; Gluck, Jessica M et al. (2016) Same-Single-Cell Analysis of Pacemaker-Specific Markers in Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Subtypes Classified by Electrophysiology. Stem Cells 34:2670-2680
Sihn, Choong-Ryoul; Kim, Hyo Jeong; Woltz, Ryan L et al. (2016) Mechanisms of Calmodulin Regulation of Different Isoforms of Kv7.4 K+ Channels. J Biol Chem 291:2499-509
Wang, Wenying; Flores, Maria Cristina Perez; Sihn, Choong-Ryoul et al. (2015) Identification of a key residue in Kv7.1 potassium channel essential for sensing external potassium ions. J Gen Physiol 145:201-12

Showing the most recent 10 out of 56 publications