It is widely accepted that an increase in [Ca2+] initiates vascular smooth muscle contraction. In addition, it is now known that the sensitivity of the contractile proteins to Ca2+ can be modulated. Agonist stimulation of vascular smooth muscle increases myofilament Ca2+ sensitivity by a G- protein dependent pathway; the steps in this pathway are however unknown. This proposal is designed to determine the pathway by which G-protein activation leads to an alteration in Ca2+ sensitivity. Specifically, this proposal will test the hypothesis that agonist activation of the smooth muscle cell initiates the following cascade of events; G-protein dependent activation of protein kinase C (PKC); PKC dependent activation of mitogen activated protein kinase kinase (MEK); MEK dependent activation of mitogen activated protein (MAP) kinase; down regulation of MLC phosphatase activity by MAP kinase catalyzed phosphorylation; and elevation of MLC phosphorylation levels at any given [Ca2+]. The following specific aims will be used to test this hypothesis; 91) To determine if activation of PKC increases while its inhibition decreases myofilament Ca2+ sensitivity; (2) To determine if MEK and MAP kinase activities are increased during agonist activation and if inhibition of PKC abolishes the increase; and (3) To determine if MLC phosphatase is phosphorylated during agonist activation and whether or not the phosphorylation site is a proline-directed serine. These studies will provide the necessary training with which to pursue my long term goal of becoming an independent academic scientist investigating vascular physiology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL009444-03
Application #
2423720
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1998-02-03
Project End
Budget Start
1998-02-03
Budget End
1998-03-08
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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