Date of Award

Summer 2003

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

Program/Concentration

Biomedical Sciences

Committee Director

Paul H. Ratz

Committee Member

Howard W. White

Committee Member

Russell Prewitt

Committee Member

Mark Elliott

Committee Member

Jeff Dupree

Abstract

KC1 causes smooth muscle contraction by elevating intracellular free calcium ([Ca2+]i), while receptor stimulation activates an additional mechanism termed Ca2+- sensitization that can involve activation of ROK and PKC. However, recent studies support the hypothesis that KC1 may also increase Ca2+-sensitivity (36). Our data showed that the PKC inhibitor, GF-109203X, did not, while the ROK inhibitor, Y-27632, did inhibit KCl-induced tonic (5’) force and myosin light chain (MLC) phosphorylation in rabbit artery. Y-27632 also inhibited Bay K-8644- and ionomycin-induced MLC phosphorylation and force, but did not inhibit KCl-induced calcium entry or peak (~15”) force. Moreover, KC1 and Bay K-8644 nearly doubled the amount o f ROK colocalized to caveolae at 30”, a time that preceded inhibition of force by Y-27632. Colocalization was not inhibited by Y-27632, but was abolished by nifedipine and the calmodulin blocker, trifluoperazine. Since, -30% of RhoA is colocalized with caveolin basally, these data suggest a novel model for Ca2+-activated Ca2+-sensitization, elicited by KC1 contraction, that involves Ca2+/cam dependent ROK translocation to caveolae and activation by RhoA.

Comments

A Dissertation Submitted to the Faculty of Old Dominion University and Eastern Virginia Medical School in Partial Fulfillment of the Requirement for the Degree of Doctor of Philosophy in Biomedical Sciences.

DOI

10.25777/7qhc-0737

ISBN

9780496549467

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