Abstract

The goals of this research program are to elucidate some of the fundamental mechanisms that control contraction of coronary arteries and to gain insights into the mechanisms by which agents can relax smooth muscle. Specifically, this application proposes to determine if there is a role for protein kinase C in the control of smooth muscle contraction. The investigators will identify specific phosphorylation patterns that are due to protein kinase C activity and use these patterns to monitor the involvement of this kinase in the events that control contraction of smooth muscle. In addition, they will determine if the stimulant effects on smooth muscle of active phorbol esters are due to effects of these agents on protein kinase C. They will also develop a """"""""state of the art"""""""" assay for diacylglycerol that is sensitive and accurate enough for use in small strips of smooth muscle. This assay will be utilized to investigate the possibility that changes in diaclyglycerol concentration control protein kinase C activity in smooth muscle, and to determine some of the factors that can alter diaclyglycerol content of intact smooth muscle.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL019325-14
Application #
3335801
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1979-05-01
Project End
1991-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
14
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212

  Publications

Guthrie, T S; Tsuji, J; Wells, J N (1991) A synthetic pseudosubstrate peptide of protein kinase C inhibits the phorbol-12,13-dibutyrate effect on permeabilized coronary artery smooth muscle. Mol Pharmacol 39:621-4
Corbin, J D; Cobb, C E; Beebe, S J et al. (1988) Mechanism and function of cAMP- and cGMP-dependent protein kinases. Adv Second Messenger Phosphoprotein Res 21:75-86
Miller-Hance, W C; Miller, J R; Wells, J N et al. (1988) Biochemical events associated with activation of smooth muscle contraction. J Biol Chem 263:13979-82
Francis, S H; Noblett, B D; Todd, B W et al. (1988) Relaxation of vascular and tracheal smooth muscle by cyclic nucleotide analogs that preferentially activate purified cGMP-dependent protein kinase. Mol Pharmacol 34:506-17
Miller, J R; Wells, J N (1987) Effects of isoproterenol on active force and Ca2+ X calmodulin-sensitive phosphodiesterase activity in porcine coronary artery. Biochem Pharmacol 36:1819-24
Sullivan, T A; Duemler, B H; Kuttesch, N J et al. (1986) Irreversible inhibition of calmodulin-sensitive cyclic nucleotide phosphodiesterase. J Cyclic Nucleotide Protein Phosphor Res 11:355-64
Miller, J R; Hawkins, D J; Wells, J N (1986) Phorbol diesters alter the contractile responses of porcine coronary artery. J Pharmacol Exp Ther 239:38-42
Keravis, T M; Duemler, B H; Wells, J N (1986) Calmodulin sensitive phosphodiesterase of porcine cerebral cortex: kinetic behavior, calmodulin activation, and stability. J Cyclic Nucleotide Protein Phosphor Res 11:365-72
Tanner, L I; Harden, T K; Wells, J N et al. (1986) Identification of the phosphodiesterase regulated by muscarinic cholinergic receptors of 1321N1 human astrocytoma cells. Mol Pharmacol 29:455-60
Saitoh, Y; Hardman, J G; Wells, J N (1985) Differences in the association of calmodulin with cyclic nucleotide phosphodiesterase in relaxed and contracted arterial strips. Biochemistry 24:1613-8