Funds are requested to continue support of studies of the pharmacology and regulation of ion channels and carrier transport proteins in the membrane of enzymatically dispersed single cardiac myocytes from guinea- pig. We will use both whole-cell and single channel recording techniques to study three major areas: (i) L-type calcium channels and their modulation by pharmacological agonists and antagonists, (ii) the properties and regulation of delayed rectifier potassium channels, and (iii) the properties and regulation of electrogenic Na-Ca exchange. During previous years of support, important new information on the mechanism of action and specificity of calcium channel agonists and antagonists was obtained. In the proposed studies we will further assess the interaction of these compounds with the inactivation process of L-type calcium channels and gain a better understanding of the role of phosphorylation and GTP binding proteins in channel inactivation. Delayed rectifier potassium channels will be studied in an attempt to better understand the gating properties of underlying channels and the intracellular regulatory pathways involved in the control of these channels by the autonomic nervous system. Finally, in recent studies, we have identified ionic currents which are generated by a Na-Ca exchange mechanism in isolated myocytes and we propose new studies to examine the relationship between these currents, changes in intracellular calcium and cell shortening. The results of these studies should provide new fundamental information about the properties of channels and exchange carriers in heart and a better understanding of excitation-contraction coupling and its modulation by pharmacological agents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL030143-08
Application #
3341189
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1987-09-01
Project End
1994-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
8
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Nevada Reno
Department
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Hume, J R; Horowitz, B (1995) A plethora of cardiac chloride conductances: molecular diversity or a related gene family. J Cardiovasc Electrophysiol 6:325-31
Collier, M L; Hume, J R (1995) Unitary chloride channels activated by protein kinase C in guinea pig ventricular myocytes. Circ Res 76:317-24
Levesque, P C; Leblanc, N; Hume, J R (1994) Release of calcium from guinea pig cardiac sarcoplasmic reticulum induced by sodium-calcium exchange. Cardiovasc Res 28:370-8
Hume, J R; Hart, P; Levesque, P C et al. (1994) Molecular physiology of CFTR Cl- channels in heart. Jpn J Physiol 44 Suppl 2:S177-82
Levesque, P C; Clark, C D; Zakarov, S I et al. (1993) Anion and cation modulation of the guinea-pig ventricular action potential during beta-adrenoceptor stimulation. Pflugers Arch 424:54-62
Horowitz, B; Tsung, S S; Hart, P et al. (1993) Alternative splicing of CFTR Cl- channels in heart. Am J Physiol 264:H2214-20
Levesque, P C; Hart, P J; Hume, J R et al. (1992) Expression of cystic fibrosis transmembrane regulator Cl- channels in heart. Circ Res 71:1002-7
Harvey, R D; Jurevicius, J A; Hume, J R (1991) Intracellular Na+ modulates the cAMP-dependent regulation of ion channels in the heart. Proc Natl Acad Sci U S A 88:6946-50
Levesque, P C; Leblanc, N; Hume, J R (1991) Role of reverse-mode Na(+)-Ca2+ exchange in excitation-contraction coupling in the heart. Ann N Y Acad Sci 639:386-97
Hume, J R; Harvey, R D (1991) Chloride conductance pathways in heart. Am J Physiol 261:C399-412

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