Important electrophysiological, pharmacological, and biochemical changes occur in myocardial cells during development of the heart, which obviously affect its functional properties. Young embryonic chick hearts have spontaneous slowly-rising, Na- and Ca-dependent, TTX-resistant action potentials. The number of fast Na channels and IK1 channels increases during development so that old embryonic chick hearts have a typical fast- rising Na-dependent action potential. Thus, the types and number of channels changes during development. Channel properties and kinetics may also change during development (long-lasting openings of Ca channels in young vs. old embryonic chick hearts). The identity and properties of the cardiac Ca channels which conduct inward current during the action potential will be examined at different stages of development. In these studies, whole-cell voltage clamp and patch clamp techniques will be used in single cells of embryonic chick and fetal rat hearts at different stages of development. In the adult heart, cAMP-dependent phosphorylation regulates the function of slow Ca channels. Phosphorylation by other kinases may also regulate channel function. For example, cGMP-, calmodulin- and phospholipid-dependent phosphorylation regulates the function of slow Ca channels. Phosphorylation by other kinases may also regulate channel function. The proposed experiments seek to determine the role of protein phosphorylation during development of the embryonic chick heart. Changes in cAMP and cGMP levels occur during development. Calmodulin levels, cGMP levels and various protein kinase activities will be measured at different stages of development. Regulation of sarcolemmal proteins by the various protein kinases will be examined to determine whether the pattern of phosphorylation changes during development, as has been shown for cAMP-dependent phosphorylation. The role of dephosphorylation will also be examined electrophysiologically and biochemically. Regulation of cation channels by G-proteins will also be evaluated. Biochemical and electrophysiological experiments will be correlated to give a better understanding of channel properties and function during development. These studies are important, since the response of the heart to pathological conditions (e.g., myocardial ischemia) and to cardioactive drugs is largely determined by the types and properties of channels present.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031942-11
Application #
3343121
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1983-07-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
11
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Zhu, L; Marvin, M J; Gardiner, A et al. (1999) Cerberus regulates left-right asymmetry of the embryonic head and heart. Curr Biol 9:931-8
Katsube, Y; Yokoshiki, H; Nguyen, L et al. (1998) Inhibition of Ca2+ current in neonatal and adult rat ventricular myocytes by the tyrosine kinase inhibitor, genistein. Eur J Pharmacol 345:309-14
Sumii, K; Imazu, M; Yamakido, M et al. (1997) Cyclic GMP-dependent protein kinase regulates the L-type calcium current in rat ventricular myocytes. Heart Vessels Suppl 12:62-5
Katsube, Y; Sperelakis, N (1996) Na+/Ca2+ exchange current: lack of effect of taurine. Eur J Pharmacol 316:97-103
Masuda, H; Sumii, K; Sperelakis, N (1996) Developmental changes in beta-adrenergic and muscarinic modulations of Ca2+ currents in fetal and neonatal ventricular cardiomyocytes of the rat. Reprod Fertil Dev 8:129-35
Yokoshiki, H; Sumii, K; Sperelakis, N (1996) Inhibition of L-type calcium current in rat ventricular cells by the tyrosine kinase inhibitor, genistein and its inactive analog, daidzein. J Mol Cell Cardiol 28:807-14
Masuda, H; Sumii, K; Sperelakis, N (1995) Long openings of calcium channels in fetal rat ventricular cardiomyocytes. Pflugers Arch 429:595-7
Conforti, L; Sumii, K; Sperelakis, N (1995) Dioctanoyl-glycerol inhibits L-type calcium current in embryonic chick cardiomyocytes independent of protein kinase C activation. J Mol Cell Cardiol 27:1219-24
Sumii, K; Sperelakis, N (1995) cGMP-dependent protein kinase regulation of the L-type Ca2+ current in rat ventricular myocytes. Circ Res 77:803-12
Haddad, G E; Sperelakis, N; Bkaily, G (1995) Regulation of the calcium slow channel by cyclic GMP dependent protein kinase in chick heart cells. Mol Cell Biochem 148:89-94

Showing the most recent 10 out of 96 publications