The key signal that contracts smooth, skeletal and cardiac muscles is an increase in [Ca2+]i. The increase in Ca2+ activates Ca2+/calmodulin-dependent myosin light chain kinase (MLCK), thereby promoting phosphorylation of myosin regulatory light chain (RLC). This phosphorylation initiates smooth muscle contractions and enhances striated (skeletal and cardiac) muscle contractions. We investigate cellular complexities of interacting signaling networks that affect myosin phosphorylation using molecular genetic approaches integrated with biophysical, biochemical and physiological measurements. Transgenic mice expressing a novel biosensor MLCK are used to determine Ca2+-dependency of activation relative to [Ca2+]i , RLC phosphorylation and contraction. Gene ablations are restricted to specific muscle cells by a tamoxifen-controlled Cre activation for measurements of contractile responsiveness in isolated tissues and in vivo. Primary hypotheses are directed to identifying the key signaling proteins essential for smooth muscle contraction that may contribute to the development of diseases involving smooth muscles. Additionally, we address the contributions of myosin phosphorylation to exercise performance of skeletal muscle and the pump function of the heart.
RESEARCH INTERESTS
Response and Adaptation to Exercise
Myosin Light Chain Kinase Function in Smooth Muscle
Biochemical and biophysical mechanisms in signal integration and protein phosphorylation involving skeletal, heart and smooth muscle contractions
RECENT PUBLICATIONS
Isotani E, Zhi G, Lau KS, Huang J, Mizuno Y, Persechini A, Geguchadze R, Kamm KE, Stull JT, "Real-time evaluation of myosin light chain kinase activation in smooth muscle tissues from a transgenic calmodulin-biosensor mouse." Proc Natl Acad Sci U S A, 101(16):6279-84, April 2004
Zhi G, Ryder JW, Huang J, Ding P, Chen Y, Zhao Y, Kamm KE, Stull JT, "Myosin light chain kinase and myosin phosphorylation effect frequency-dependent potentiation of skeletal muscle contraction." Proc Natl Acad Sci U S A, 102(48):17519-24, November 2005
Ryder, J. W., Lau, K. S., Kamm, K. E., and Stull, J. T., "Enhanced Skeletal Muscle Contraction with Myosin Light Chain Phosphorylation by a Calmodulin-sensing Kinase" J. Biol. Chem., 282:20447-20454, 2007
He W-Q, Peng Y-J, Zhang W-C, Lv N, Tang J, Chen C, Zhang C-H, Gao S, Chen H-Q, Zhi G, Feil R, Kamm KE, Stull JT, Gao X, and Zhu M-S, "Myosin Light Chain Kinase Is Central to Smooth Muscle Contraction and Required for Gastrointestinal Motility in Mice" Gastroenterology, 135:610-620, 2008
SIGNIFICANT PUBLICATIONS
Kamm KE, Stull JT, "Activation of smooth muscle contraction: relation between myosin phosphorylation and stiffness" Science, 232(4746):80-2, April 1986
Sweeney HL, Bowman BF, Stull JT, "Myosin light chain phosphorylation in vertebrate striated muscle: regulation and function" Am J Physiol, 264(5 Pt 1):C1085-95, May 1993
Smith L, Su X, Lin P, Zhi G, Stull JT, "Identification of a novel actin binding motif in smooth muscle myosin light chain kinase" J Biol Chem, 274(41):29433-8, October 1999
Kamm KE, Stull JT, "The function of myosin and myosin light chain kinase phosphorylation in smooth muscle" Annu Rev Pharmacol Toxicol, 25:593-620, 1985
Krueger JK, Olah GA, Rokop SE, Zhi G, Stull JT, Trewhella J, "Structures of calmodulin and a functional myosin light chain kinase in the activated complex: a neutron scattering study" Biochemistry, 36(20):6017-23, May 1997
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