The vertebrate heart contracts spontaneously, but the force and frequency of contraction are increased by norepinephrine (NE) released from sympathetic nerves and decreased by acetylcholine (ACh) released from parasympathetic nerves. At the molecular level, these transmiters act upon several different effector systems. The effects on beat frequency are produced by modulation of several kinds of ionic channels in the plasma membrane and consequent alteration of pacemaker currents. Effects on contractile force are mediated by changes in myosin cross-bridge activity which is regulated by (1) the influx of Ca during the action potential, (2) Ca sequestration and release by the sarcoplasmic reticulum (SR), and (3) the functioning of proteins in the contractile apparatus. The molecular mechanisms underlying these effects, however, are poorly understood. The overall goal of this research is to understand the molecular mechanisms which underly neural (particularly parasympathetic) control of the heart. We would like to understand how the binding of ACh to receptors is transmitted to different effector systems (ion channels, contractile apparatus, etc.), how the different effectors contribute quantitatively to changes in contractile force and frequency, and whether the opposing effects of sympathetic and parasympathetic activity are mediated through opposite effects on the same effector systems. This research will address three specific questions. (1) What are the molecular mechanisms underlying the increase in K+ conductance (hyperpolarization) produced by ACh in the heart. Electrophysiological techniques will be used to determine the mechanisms which are responsible for the long duration of this response. (2) Does phosphorylation of the myofibrillar protein, C-protein, play a role in regulating the force of cardiac contraction? Biochemical experiments will correlate phosphorylation of this protein with contractile activity of the heart. (3) What are the molecular mechanisms by which ACh stimulates dephosphorylation of C-protein? These studies hopefully will increase our understanding of the mechanisms by which ACh regulates heartbeat.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL021195-11
Application #
3336420
Study Section
Physiology Study Section (PHY)
Project Start
1977-08-01
Project End
1988-07-31
Budget Start
1987-08-01
Budget End
1988-07-31
Support Year
11
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Kuruma, A; Hirayama, Y; Hartzell, H C (2000) A hyperpolarization- and acid-activated nonselective cation current in Xenopus oocytes. Am J Physiol Cell Physiol 279:C1401-13
Kuruma, A; Hartzell, H C (1999) Dynamics of calcium regulation of chloride currents in Xenopus oocytes. Am J Physiol 276:C161-75
Machaca, K; HC Hartzell (1999) Reversible Ca gradients between the subplasmalemma and cytosol differentially activate Ca-dependent Cl currents. J Gen Physiol 113:249-66
Machaca, K; Hartzell, H C (1999) Adenophostin A and inositol 1,4,5-trisphosphate differentially activate Cl- currents in Xenopus oocytes because of disparate Ca2+ release kinetics. J Biol Chem 274:4824-31
Hirayama, Y; Hartzell, H C (1997) Effects of protein phosphatase and kinase inhibitors on Ca2+ and Cl- currents in guinea pig ventricular myocytes. Mol Pharmacol 52:725-34
Hartzell, H C; Rinderknecht, A (1996) Calphostin C, a widely used protein kinase C inhibitor, directly and potently blocks L-type Ca channels. Am J Physiol 270:C1293-9
Hartzell, H C; Hirayama, Y; Petit-Jacques, J (1995) Effects of protein phosphatase and kinase inhibitors on the cardiac L-type Ca current suggest two sites are phosphorylated by protein kinase A and another protein kinase. J Gen Physiol 106:393-414
Hartzell, H C; Duchatelle-Gourdon, I (1993) Regulation of the cardiac delayed rectifier K current by neurotransmitters and magnesium. Cardiovasc Drugs Ther 7 Suppl 3:547-54
Frace, A M; Mery, P F; Fischmeister, R et al. (1993) Rate-limiting steps in the beta-adrenergic stimulation of cardiac calcium current. J Gen Physiol 101:337-53
Frace, A M; Hartzell, H C (1993) Opposite effects of phosphatase inhibitors on L-type calcium and delayed rectifier currents in frog cardiac myocytes. J Physiol 472:305-26

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