Cardiovascular disease is the leading cause of morbidity and mortality in the United States and in our veteran population. During the last funding cycle, we have identified several atrial-specifi ion channels including Cav1.3 (1D) L-type Ca2+ channel and small conductance Ca2+-activated K+ channels (SK or KCa2 channels) which play critical roles in the function of atrial myocytes as well as sinoatrial (SA) and atrioventricular (AV) nodes. Of clinical importance, we have demonstrated that SK channels are expressed and contribute significantly to the repolarization process in human atrial myocytes. For the current competing renewal application, we will focus our effort on the subcellular regulation of Ca2+ channels in ventricular myocytes and pacemaking cells. Embedded in our findings and the proposed project are relevant paradigm shifts that may be exploited in developing specific drugs for the treatment of cardiac arrhythmias. Specifically, we will test the central hypothesis that there is isoform-specific differential regulation of L-type Ca2+ current in ventricular myocytes and pacemaking cells by distinct isoforms of adenylyl cyclases (ACs). We will utilize new emerging techniques of live-cell imaging coupled with fluorescence resonance energy transfer (FRET)-based cAMP and protein kinase A (PKA) sensors to directly decipher the distinct subcellular localization and activities of different isoforms of ACs not only in ventricular myocytes but also in pacemaking cells. Indeed, we will take advantage of multidisciplinary techniques including in vivo and in vitro electrophysiologic recordings, live-cell imaging, and molecular modeling to determine the subcellular regulation of Ca2+ channels through distinct isoforms of ACs. Our proposed studies will expand our understanding of the specific subcellular localization and regulation of individual Ca2+ channels and how they might coordinate to mediate normal cardiac rhythm in vivo. Understanding the molecular and subcellular regulation of Ca2+ channels in the heart will set the stage for a new and more mechanistic approach for the treatment of cardiac arrhythmias and SA and AV node dysfunction, a common problem encountered in our veteran population.

Public Health Relevance

Cardiovascular diseases continue to represent the most common cause of morbidity and mortality in our veteran patients. Moreover, the incidence is increasing due to our aging population. Our present study proposes to use a combination of molecular, biochemical and imaging techniques, electrophysiologic studies as well as molecular modeling to define the molecular and subcellular regulation of Ca2+ channels in ventricular myocytes and pacemaking tissues. Understanding the regulation of Ca2+ channels in the heart will set the stage for a new and more mechanistic approach for the therapy of cardiac arrhythmias and pacemaking cell dysfunction, a common problem encountered in our VA population. More rational design of channel-specific ligands becomes a possibility. Indeed, new insights into how Ca2+ channels may be regulated will offer a unique therapeutic opportunity to directly modify pacemaking cells without interfering with ventricular myocytes.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX000576-05A1
Application #
8819408
Study Section
Cardiovascular Studies A (CARA)
Project Start
2009-10-01
Project End
2019-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
VA Northern California Health Care System
Department
Type
DUNS #
127349889
City
Mather
State
CA
Country
United States
Zip Code
95655
Yeo, Khung-Keong; Armstrong, Ehrin J; López, Javier E et al. (2018) Aspirin and clopidogrel high on-treatment platelet reactivity and genetic predictors in peripheral arterial disease. Catheter Cardiovasc Interv 91:1308-1317
Hegyi, Bence; Bossuyt, Julie; Griffiths, Leigh G et al. (2018) Complex electrophysiological remodeling in postinfarction ischemic heart failure. Proc Natl Acad Sci U S A 115:E3036-E3044
Zhang, Xiao-Dong; Coulibaly, Zana A; Chen, Wei Chun et al. (2018) Coupling of SK channels, L-type Ca2+ channels, and ryanodine receptors in cardiomyocytes. Sci Rep 8:4670
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
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
Fu, Qin; Hu, Yuting; Wang, Qingtong et al. (2017) High-fat diet induces protein kinase A and G-protein receptor kinase phosphorylation of ?2 -adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts. J Physiol 595:1973-1986
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
Chiamvimonvat, Nipavan; Chen-Izu, Ye; Clancy, Colleen E et al. (2017) Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics. J Physiol 595:2229-2252
Kennedy, Matthew; Bers, Donald M; Chiamvimonvat, Nipavan et al. (2017) Dynamical effects of calcium-sensitive potassium currents on voltage and calcium alternans. J Physiol 595:2285-2297

Showing the most recent 10 out of 56 publications