Date of Award

2006

Degree Name

Doctor of Philosophy

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Gary L. Wright

Second Advisor

Michael E. Fultz

Third Advisor

Elsa I. Mangiarua

Abstract

A complete understanding of the mechanisms underlying smooth muscle contractility has proven elusive due to the many interacting factors thought to influence contractile behavior in this muscle type. One such factor, protein kinase Cα (PKCα), is proposed to play a central role in both the activation and modulation of smooth muscle contraction. PKCα is activated through a G-protein coupled receptor and is subsequently translocated to its site of action. Although the mechanisms regulating PKCα site specific translocation are not completely understood, it is thought that this process is essential for PKCα specificity of action within the cell. In chapter II we discuss our research demonstrating a PKCα/β-tubulin relationship in the contracting smooth muscle cell. Here, we show for the first time that PKCα translocation is dependent on an intact system of microtubules and propose the hypothesis of microtubular involvement in PKCαtranslocation. Activation of PKCα in contracting smooth muscle is thought to result in the phosphorylation of several proteins which could be important in contraction. One such protein, calponin, is known to influence smooth muscle contractility but its mechanism of action is not clear. In chapter III, we discuss our research showing the formation of a PKCα/calponin complex in contracting smooth muscle with associated losses in α-actin stress fibers and cytoskeletal remodeling. Based on this work, we propose that calponin plays a major role in the stabilization of stress fibers and that the release from calponin cross-linking of actin filaments provides a mechanism enabling actin filament sliding and subsequent cytoskeletal remodeling.

Subject

Vascular smooth muscle - Contraction

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