Cardiac myocyte excitation-contraction coupling, the process that enables the heart to contract and relax, involves many finely-tuned systems, nearly all of them dependent on intracellular Ca ([Ca]i). Intracellular Na concentration ([Na]i) critically regulates [Ca]i, and thus cardiac contraction, through the Na/Ca exchanger, a membrane transporter that is the main route for Ca extrusion from cardiac muscle cells. Research in my laboratory focuses on Ca and Na regulation in the normal and diseased heart and understanding the cellular bases of triggered ventricular arrhythmias.
Ongoing projects aim to 1) elucidate the mechanisms responsible for Ca dysregulation and arrhythmias induced by loss-of-function of ankyrin-B, a multivalent "adaptor" protein that targets and tethers select membrane proteins to the cytoskeleton; 2) determine how cardiac Ca and Na regulation is altered in diabetic heart disease and how this affects the propensity for arrhythmias; 3) reveal how Ca and Na are regulated in subcellular microdomains in cardiac myocytes; and (4) understand mechanistically the association and functional interaction between Na/K pump and phospholemman in the heart and its role in modulating contractility and arrhythmogenesis.
For all these projects we combine electrophysiology, fluorescence microscopy, biochemistry and molecular biology techniques in ventricular myocytes isolated from wild-type and transgenic animal models.
Despa S, Islam MA, Weber CR, Pogwizd SM, Bers DM. (2002) Intracellular Na+ Concentration is Elevated in Heart Failure, but Na/K-Pump Function is Unchanged. Circulation 105, 2543-2548.
Despa S, Brette F, Orchard CH, Bers DM. (2003) Na/Ca exchange and Na/K-ATPase function are equally concentrated in transverse tubules of rat ventricular myocytes. Biophys J. 85, 3388-3396.
Despa S, Bossuyt J, Han F, Ginsburg KS, Jia LG, Kutchai H, Tucker AL, Bers DM. (2005) Phospholemman -phosphorylation mediates the Beta-adrenergic effects on Na/K pump function in cardiac myocytes. Circ Res 97, 252-259.
Bossuyt J, Despa S, Martin JL, Bers DM. (2006) Phospholemman Phosphorylation alters its association with the Na-pump as assessed by FRET. J Biol Chem. 281, 32765-32773.
Despa S, Bers DM. (2007) Functional analysis of Na+/K+-ATPase isoform distribution in rat ventricular myocytes. Am J Physiol Cell Physiol. 293, C321-C327.
Despa S, Tucker AL, Bers DM. (2008) PLM-mediated activation of Na/K – ATPase limits [Na]i and inotropic state during Beta-adrenergic stimulation in mouse ventricular myocytes. Circulation 117, 1849-1855.
Bossuyt J, Despa S, Han F, Hou Z, Robia SL, Lingrel JB, Bers DM. Isoform specificity of the Na/K-ATPase association and regulation by phospholemman. J Biol Chem. 2009;284:26749-57.
Bers DM, Despa S. Na/K-ATPase – an integral player in the adrenergic fight-or-flight response. Trends Cardiovasc Med. 2009, 19:111-118.
Despa S, Margulies KB, Chen L, Knowlton AA, Havel PJ, Taegtmeyer H, Bers DM, Despa F. Hyperamylinemia contributes to heart dysfunction in obesity and diabetes, a study in humans and rats. Circ. Res. 2012, 110:598-608.
Camors E, Mohler PJ, Bers DM, Despa S. Ankyrin-B reduction alters Na and Ca transport promoting cardiac myocyte arrhythmic activity. J. Mol. Cell Cardiol. 2012, 52:1240-1248.