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Zheng Liu, Ph.D.
The focus of Dr. Liu's laboratory is on the structure and function of a calcium ion channel in cardiac muscle. Calcium ions are second messengers in signaling pathways in all types of cells. In the heart, they regulate cardiac muscle contraction, electrical signals that determine the cardiac rhythm, and cell growth pathways. One of the major calcium channels responsible for calcium release from intracellular stores is the ryanodine receptor. The ryanodine receptor plays a crucial role in muscle excitation-contraction coupling, a process in which neuron-induced depolarization of the plasma membrane causes ryanodine receptor molecules to release Ca2+ from the sarcoplasmic reticulum; the resulting increase in cytoplasmic [Ca2+] activates the myofilaments so as to generate muscle contraction. Abnormal calcium release through mutant cardiac muscle ryanodine receptors (RyR2) is directly involved in two inherited forms of cardiac arrhythmias.
The long-term goals include determination of a high-resolution three-dimensional (3D) structural model for RyR2, a description of the conformational dynamics of RyR2, and understanding how structure and conformation are affected by the natural occurring mutations in RyR2 and by pharmacologic modulators of RyR2s. Dr. Liu's laboratory combines highly complementary and synergistic biophysical techniques of 3D single particle cryo-electron microscopy (cryo-EM) and fluorescence resonance energy transfer (FRET), in conjunction with homology modeling and molecular dynamics flexible fitting, to determine the 3D structure of RyR2, and to characterize their conformation dynamics.
The Liu lab is particularly interested in the position of the disease-causing mutations in the RyR2 and how they cause the abnormalities in the conformational dynamics of the mutant RyR2s; in the defective interactions between RyR2's structural domains and between the receptor and its modulators that physiologically regulate channel functions. The information, in structural terms, will help us to comprehend the role of RyR2 in cardiac excitation-contraction coupling, and how mutant RyR2 dysfunction leads to sudden cardiac death, which in turn will directly contribute to rational design of novel therapeutic strategies and the eventual development of new drugs.