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Excitation-contraction coupling, Ca 2+ and Na + regulation in the normal and diseased heart;

Research Interest Sanda Despa, PhD Department of Pharmacology. Excitation-contraction coupling, Ca 2+ and Na + regulation in the normal and diseased heart;  C ellular bases of triggered ventricular arrhythmias. RyR. Ca. NCX. 3Na. Cardiac excitation-contraction coupling. 3Na. Na.

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Excitation-contraction coupling, Ca 2+ and Na + regulation in the normal and diseased heart;

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  1. Research Interest Sanda Despa, PhD Department of Pharmacology • Excitation-contraction coupling, Ca2+ and Na+ regulation in the normal • and diseased heart; •  Cellular bases of triggered ventricular arrhythmias

  2. RyR Ca NCX 3Na Cardiac excitation-contraction coupling 3Na Na 2K Sarcolemma ATP ATP NCX PLM Ca 3Na ICa Ca Ca ATP SR Ca PLB T-Tubule

  3. RyR Ca NCX 3Na Cardiac excitation-contraction coupling 3Na Na 2K Sarcolemma ATP ATP NCX PLM Ca 3Na ICa Ca Ca ATP SR Ca PLB T-Tubule

  4. RyR Ca NCX 3Na Contraction of the heart 3Na Na 2K Sarcolemma NCX ATP ATP PLM Ca 3Na ICa Ca Ca ATP SR Ca PLB T-Tubule

  5. RyR Ca NCX 3Na Relaxation of the heart 3Na Na 2K ATP ATP NCX Sarcolemma PLM Ca 3Na ICa Ca Ca Ca ATP SR Ca PLB T-Tubule

  6. Ca2+ and contraction-relaxation of a cardiac myocyte Rat ventricular myocyte loaded with a Ca2+-sensitive fluorescent indicator

  7. Project 1: Ca dysregulation and arrhythmias induced by loss-of-function of ankyrin B Ankyrin-B = multivalent “adaptor” protein that targets select membrane proteins to the cytoskeleton

  8. E1425G mutation Long QT4 syndrome Ventricular arrhythmias Q-T DII DIII * * * 1 sec QTc= 450 ms in symptomatic patients (normal QTc<420 ms in men; <440 ms in women) (Schott JJ et al., Am. J. Hum. Genet. 1994) Long QT syndromes in humans Ankyrin-B loss of function mutations lead to long QT4 syndrome and ventricular arrhythmias in humans 1 sec

  9. Decreased NCX and NKA expression, particularly at the T-tubules, in AnkB+/- myocytes AnkB+/- mice = mice heterozygous for a null mutation in ankyrin-B gene. (Mohler et al., Nature 2003)

  10. Reduced NCX and NKA function in AnkB+/-myocytes NCX function Caffeine NKA function Camors, …, Despa. JMCC, 2012

  11. Similar [Na]i and diastolic [Ca]i in myocytes from AnkB+/- and WT mice [Na]i Diastolic [Ca]i Resting Pacing Camors, …, Despa. JMCC, 2012

  12. Larger Ca transients, SR Ca load & fractional release in AnkB+/- mice Camors, …, Despa. JMCC, 2012

  13. Enhanced Ca spark frequency in intactAnkB+/- mice 1 s WT 250 0 Caffeine AnkB+/- 40 µm 1 mM Ca Tyrode 0 Na/ 0 Ca Tyrode Caffeine 250 10 µm 200 ms 0 Camors, …, Despa. JMCC, 2012

  14. More pro-arrhythmic Ca waves in AnkB+/- myocytes AnkB+/- Control condition ISO (1 µM) 60 % 20 % 10 % Camors, …, Despa. JMCC, 2012

  15. Work in progress; Questions: • What causes the increased propensity for Ca sparks and waves in AnkB+/- myocytes? •  Altered cytosolic RyR regulation? WT AnkB+/- diastolic Ca NKA-α1 diastolic Ca AnkB [Ca] Ca ATP RyR Ca K Ca NKA-2 Nuclear Nuclear Na T-tubule NCX Ca T-tubule Ca Ca ATP Cleft RyR envelope envelope Ca Ca Cleft Ca P IP3R IP3R B56

  16. Work in progress; Questions: 2. Does AnkB proteolysis by calpain lead to a cardiac phenotype similar to that caused by genetic AnkB loss-of-function? Protein expression mRNA level AnkB protein but not mRNA is reduced in the infarct border zone after MI Hundt et al., Cardiovasc Res. 2009;81:742

  17. Work in progress; Questions: 2. Does AnkB proteolysis by calpain lead to a cardiac phenotype similar to that caused by genetic AnkB loss-of-function? AnkB & NKA protein expression are reduced following ischemia/reperfusion; the effect is prevented by calpain inhibition NKA Inserte et al., Circ Res 2005;97:465. • How does calpain activation affect the protein expression, subcellular distribution and function of AnkB, NCX and NKA? • What is the role of AnkB proteolysis by calpain in the structural and electrical remodeling of the heart following ischemia/reperfusion?

  18. Project 2: Electrical remodeling and arrhythmias in diabetic heart disease •  How is Ca cycling altered in diabetic heart disease? Timeline! • Is [Na]i altered in diabetic heart disease? Does this further alter the cardiac metabolism? • ROS production →  slowly inactivating INa →  [Na]i →  [Ca]m → ATP •  Electrical remodeling & occurrence of arrhythmias in diabetic hearts Pre-diabetic stage Diabetic stage Long QT

  19. Acknowledgments University of California Davis Emmanuel Camors Kevin Voelker Florin Despa Samuel Galice Jeffrey Elliot Kaleena Jackson Brian Koch Donald M. Bers Kenneth Ginsburg Khana Dao Ohio State University Peter Mohler University of California Los Angeles Enrico Stefani Yong Wu University of Cincinnati Jerry B. Lingrel University of Manchester Fabian Brette Funding from NIH & AHA

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