Type of Document	Dissertation
Author	Schoffstall, Brenda
Author's Email Address	bschoff@sb.fsu.edu
URN	etd-10272006-190157
Title	MODULATORS OF MYOSIN ACTIVITY AND ACTOMYOSIN INTERACTION: POTENTIAL FOR 2’-DEOXY-ATP (dATP) AS A POSITIVE INOTROPE IN CARDIAC MUSCLE
Degree	PhD
Department	Molecular Biophysics, Institute of
Advisory Committee	Advisor Name Title Thomas Keller, Ph.D. Committee Chair Kenneth Taylor, Ph.D. Committee Member Oliver Steinbock Committee Member P. Bryant Chase, Ph.D. Committee Member Timothy Moerland, Ph.D. Committee Member
Keywords	myosin actin inotrope ATP cardiac muscle
Date of Defense	2006-10-13
Availability	unrestricted
Abstract Myosin activity and actomyosin interaction play key roles in normal and pathological cardiac muscle contraction. Factors that modulate actomyosin have the potential to exert changes in cardiac contraction that may be necessary for normal cardiac function, or could be beneficial for the treatment of pathological cardiac function. Here we describe an investigation into both intrinsic factors that may contribute to the normal role of actomyosin in muscle contraction, as well as extrinsic factors, in the form of drugs, compounds, or gene therapy, that have potential for therapeutic treatment of cardiac disease states due to possible modulations of myosin activity or actomyosin interaction. We found that changes in myosin isoform that sometimes accompany cardiac disease states alter the kinetics of muscle contraction without alteration to the calcium sensitivity of contractile parameters. We also found that there may exist an important protein interaction between the thin filament protein troponin and myosin during normal muscle contraction. This interaction could have negative implications if mutations at that interaction site alter normal contraction. We found that the anti-hypertrophic drug rapamycin does not exert its cardiac anti-hypertrophy via its direct effects on the myofilament proteins. This suggests that rapamycin’s activity rather may control signaling pathways involved in cardiac contraction. We found that low, but supra-physiological dATP/ATP ratios enhanced cardiac contractility in vitro, presumably due to recruitment of large numbers of force-producing actomyosin cross-bridges and an apparent high affinity of dATP for myosin. We showed that there may exist an “optimal” intracellular [dATP] that has the potential to enhance cardiac contractility in living cardiac cells. These results suggested that methods for increasing [dATP] in living cardiac tissue should be explored. Clearly, it is important to understand and investigate factors that directly modulate myosin activity and actomyosin interaction in order to contribute to future treatments for pathological cardiac conditions.
Files	Filename       Size       Approximate Download Time (Hours:Minutes:Seconds)     28.8 Modem   56K Modem   ISDN (64 Kb)   ISDN (128 Kb)   Higher-speed Access    BS_Schoffstall_diss.pdf 7.75 Mb 00:35:53 00:18:27 00:16:08 00:08:04 00:00:41