The vertebrate heart contracts spontaneously, but the force and frequency of contration are increased by norepinephrine (NE) release from sympathetic nerves and acetylcholine (ACh) released from parasympathetic nerves. These transmitters act upon several different effector systems including several different kinds of ion channels in the plasma membrane, the sarcoplasmic reticulum, and proteins in the contractile apparatus. The mechanism of action of NE is relatively well understood: NE increases contractility by stimulating adenylate cyclase which in turn activates the cAMP-dependent protein kinase that phosphorylates the appropriate effector proteins. The molecular mechanisms of action of ACh, on the other hand, are less well understood. The overall goal of this research will continue to be to elucidate the molecular mechanisms which underlie neural (particularly parasympathetic) and hormonal control of the heart. We would like to understand how the binding of ACh to receptors is transmitted to different effector systems, the nature of the """"""""second messenger"""""""" systems invovled, and the role of each of the effector systems in regulating contraction. In this next 5-year period, we plan to focus heavily upon regulation of the trans-sarcolemmal calcium current (ICa), because this current plays a central role in determining the force of cardiac contraction. In addition, we will pursue experiments on phosphorylation of C-protein. The research will address 4 specific questions. (1) What is the mechanisms of cGMP action on ICa? We have previously shown that intracellular perfusion with cGMP decreases I Ca under certain conditions, and we have hypothesized that this decrease is mediated by a cGMP-stimulated phosphodiesterase. This hypothesis wil be tested extensively. (2) What are the mechanisms of ACh action on ICa? Does ACh act only by inhibiting adenylate cyclase, or are there other modes of ACh action? (3) Does ACh produce its positive inotropic effects on the heart by stimulating phosphoinositide metabolism and increasing ICa? (4) Are ICa and C-protein and troponin-1 phosphorylation controlled coordinately? It is hoped that these studies will provide new insights into neural control of cardiac function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL021195-18
Application #
2215442
Study Section
Special Emphasis Panel (NSS)
Project Start
1977-08-01
Project End
1998-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
18
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Emory University
Department
Anatomy/Cell Biology
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
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
Mery, P F; Frace, A M; Hartzell, H C et al. (1993) A comparative analysis of the time course of cardiac Ca2+ current response to rapid applications of beta-adrenergic and dihydropyridine agonists. Naunyn Schmiedebergs Arch Pharmacol 348:197-206
Parsons, T D; Hartzell, H C (1993) Regulation of Ca2+ current in frog ventricular cardiomyocytes by guanosine 5'-triphosphate analogues and isoproterenol. J Gen Physiol 102:525-49

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