Two Kinases That Keep Heart Beating May Be Targets For Heart Failure Therapy

Dr-Audrey-Chang credit: UT Southwestern

Dr. Audrey Chang Interview with:
Dr. Audrey Chang, PhD
Kamm-Stull Lab
UT Southwestern Medical Center What is the background for this study? What are the main findings?

Response: The heart is a singular kind of muscle that contracts and relaxes continuously over a lifetime to pump blood to the body’s organs. Contractions depend on a motor protein myosin pulling on actin filaments in specialized structures. Heart contraction is improved when myosin has a phosphate molecule attached to it (phosphorylation), and a constant amount of phosphorylation is essential for normal heart function. The amount of phosphorylation necessary for optimal cardiac performance is maintained by a balance in the activities of myosin kinase enzymes that add the phosphate and an opposing phosphatase enzyme that removes the phosphate. If the amount of phosphorylation is too low, heart failure results. Animal models with increased myosin phosphorylation have enhanced cardiac performance that resist stresses that cause heart failure.

In this recent study reported in PNAS, a new kinase that phosphorylates myosin in heart muscle, MLCK4, was discovered and its crystal structure reported, a first for any myosin kinase family member. Compared to distinct myosin kinases in other kinds of muscles (skeletal and smooth), this cardiac-specific kinase lacks a conserved regulatory segment that inhibits kinase activity consistent with biochemical studies that it is always turned on. Additionally, another related myosin kinase found only in heart muscle (MLCK3) contains a modified regulatory segment, allowing partial activity enhanced by the calcium modulator protein, calmodulin. Thus, both myosin kinases unique to cardiac muscle provide phosphate to myosin in normal beating hearts to optimize performance and prevent heart failure induced by stresses. What should readers take away from your report?

Response: Although the importance of myosin phosphorylation for optimal heart function has been appreciated, key insights as to how it is regulated have been lacking. Our discoveries, made by integrating structural information for MLCK4 and biochemical analyses of MLCKs in the heart, led us to conclude that constant activities of the cardiac kinases contribute to the constitutive phosphorylation of cardiac myosin in beating hearts necessary for normal function. What recommendations do you have for future research as a result of this study?

Response: The heart-specific expression of these kinases, and the linkage between low myosin phosphorylation and heart failure makes targeting of these cardiac myosin kinases to improve cardiac function compelling. Additional studies should be undertaken to define distinct signaling pathways that fine tune kinase activities with the goal of targeting these two kinases therapeutically to improve myosin phosphorylation in heart failure. Is there anything else you would like to add?

Response: When precautions are taken to minimize dephosphorylation and maximize protein solubilization with tissue processing, measurements of myosin phosphorylation in various animal models have shown that the amount measured can be an indicator for cardiac performance. Thus, documenting the extent of MLCK3 and MLCK4 expression and myosin phosphorylation in cardiac samples could provide insights into the pathology of the cardiac disease. Investigators should 1) follow proven sample preparation protocols for measurements of myosin phosphorylation for accurate quantification, and 2) not overlook the regulators of myosin phosphorylation in screens/analyses for genetic polymorphisms associated with heart failure. Thank you for your contribution to the community.

Citation:Audrey N. Chang, Pravin Mahajan, Stefan Knapp, Hannah Barton, H. Lee Sweeney, Kristine E. Kamm, James T. Stull. Cardiac myosin light chain is phosphorylated by Ca2 /calmodulin-dependent and -independent kinase activities. Proceedings of the National Academy of Sciences, 2016; 201600633 DOI: 10.1073/pnas.1600633113

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.
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