Normal excitation-contraction (EC) coupling in mammalian cardiac cells requires the coordinated release of calcium (Ca2+) from the sarcoplasmic reticulum (SR). In mammalian ventricular cells, the extensive transverse-tubular (t-tubular) system conducts electrical depolarization rapidly to the cell interior that triggers a near synchronous release of C2+ from the SR and subsequent activation of the myofibrils throughout the cell. Because atrial cells lack an extensive t-tubular network, the coordination of SR Ca2+-release and contraction in atrial cells must depend on an entirely different cellular process.
The aim of the proposed research is to answer the question, """"""""What is (are) the cellular mechanism(s) responsible for the transduction of membrane depolarization to subsequent contraction in cardiac atrial cells?"""""""" The overall hypotheses of this proposed project are (1) that the mechanism of coupling Ca2+-entry through L-type Ca2+ channels and Ca2+-release from the SR at the peripheral couplings of atrial cells is the same as that which occurs at the t-tubular-junctional SR region in ventricular cells, and (2) that because of the absence of a well-organized t-tubular system in atrial cells, the normal physiological mechanisms of SR Ca2+-release away from the peripheral couplings are entirely different.
Specific aim 1 tests the hypothesis that the relationship between Ca2+-entry via L-type Ca2+ channels and Ca2+-release from the SR at the peripheral couplings in atrial cells is identical to that in the t-tubular-junctional SR region of ventricular cells.
Specific aim 2 tests the hypothesis that both propagated and non-propagated Ca2+-release occur in atrial cells and that the type of Ca2+-release is determined by SR Ca2+-load, ryanodine receptor (RyR) Ca2+-sensitivity, and the magnitude and duration of the Ca2+-entry through L-type Ca2+ channels.
Specific aim 3 tests the hypothesis that the magnitude and velocity of contraction depends on the type of Ca2+-release (non-propagating or propagating) and the """"""""diffusional"""""""" size of the cell. We hypothesize that an increase in the cell circumference triggers a switch between non-propagating and propagating Ca2+-release, thereby providing a means for maintaining the speed and magnitude of contraction despite differences in cell size. Specifically, we test (1) that non-propagating Ca2+-release can elicit rapid and large contractions in atrial cells with small circumference. (2) Propagating Ca2+-waves are needed to cause rapid and large contractions in atrial cells with a large circumference. (3) The transverse axial tubular system (TATS), by reducing diffusional distances, allows non-propagating Ca2+-release to cause rapid and large contractions in large atrial cells. This proposal uniquely combines mathematical modeling, cellular electrophysiology and Ca2+ imaging and will provide a quantitative understanding of Ca2+ homeostasis in cardiac atrial cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL071865-03
Application #
7122602
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
2003-08-01
Project End
2007-07-31
Budget Start
2005-02-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$275,000
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Sumandea, C Amelia; Garcia-Cazarin, Mary L; Bozio, Catherine H et al. (2011) Cardiac troponin T, a sarcomeric AKAP, tethers protein kinase A at the myofilaments. J Biol Chem 286:530-41
Sfichi-Duke, Liliana; Garcia-Cazarin, Mary L; Sumandea, C Amelia et al. (2010) Cardiomyopathy-causing deletion K210 in cardiac troponin T alters phosphorylation propensity of sarcomeric proteins. J Mol Cell Cardiol 48:934-42
Kapur, Sunil; Aistrup, Gary L; Sharma, Rohan et al. (2010) Early development of intracellular calcium cycling defects in intact hearts of spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 299:H1843-53
Sumandea, C Amelia; Balke, C William (2009) Funding opportunities for investigators in the early stages of career development. Circulation 119:1320-7
Sumandea, Marius P; Rybin, Vitalyi O; Hinken, Aaron C et al. (2008) Tyrosine phosphorylation modifies protein kinase C delta-dependent phosphorylation of cardiac troponin I. J Biol Chem 283:22680-9
Chen, Ling; Zhang, Jin; Gan, Tracey X et al. (2008) Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia. J Appl Physiol 104:218-23
Armoundas, Antonis A; Rose, Jochen; Aggarwal, Rajesh et al. (2007) Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: primary defects in SR Ca2+ uptake and release mechanisms. Am J Physiol Heart Circ Physiol 292:H1607-18
Fedorov, Vadim V; Lozinsky, Ilya T; Sosunov, Eugene A et al. (2007) Application of blebbistatin as an excitation-contraction uncoupler for electrophysiologic study of rat and rabbit hearts. Heart Rhythm 4:619-26
Chen-Izu, Ye; Chen, Ling; Banyasz, Tamas et al. (2007) Hypertension-induced remodeling of cardiac excitation-contraction coupling in ventricular myocytes occurs prior to hypertrophy development. Am J Physiol Heart Circ Physiol 293:H3301-10
Barrows, Brian R; Azimzadeh, Agnes M; McCulle, Stacey L et al. (2007) Robust gene expression with amplified RNA from biopsy-sized human heart tissue. J Mol Cell Cardiol 42:260-4

Showing the most recent 10 out of 17 publications