JHU biomedical engineering primary faculty
David T. Yue, MD, PhD
Professor of Biomedical Engineering and Neuroscience
Co-Director, Ph.D. Program
Office: Ross 713-715
Lab: Calcium Signals Laboratory
B.A., Biochemical Science, Harvard University, 1979
Ph.D., Biomedical Engineering, Johns Hopkins University, 1987
M.D., Johns Hopkins University, 1987
Molecular Engineering Physiology of Ca2+ Channels and Ca2+ Signals
Intracellular Ca2+ signals comprise a lingua franca of life at the microscopic scale. For example, Ca2+ inflow through Ca2+ channels (a voltage-controlled, Ca2+-entry porthole into cells) starts a chain of events leading to initiation of the heartbeat, or even to the neuro-synaptic transmission underlying our very thoughts. Moreover, longer-term changes in [Ca2+] control gene expression. It is no wonder that Ca2+ signals are as critical and ubiquitous to biological systems, as are voltage signals to electronic circuits. Much of our research therefore focuses on the “transistors” of Ca2+ signaling?voltage-gated Ca2+ channels. Unmasking their secrets critically deepens understanding of normal biology, and promises to reveal new therapies for disease.
Ca2+ signals research provides a remarkable opportunity for the fruitful combination of mathematics, engineering, and molecular experimentation. Channel functions can be quantitatively probed with patch-clamp electrophysiology (1-4) and a biological fluorescence technique called FRET (3). The latter approach offers a dynamic readout of molecular motions in single living cells. Molecular biology (1-4), biochemistry (1-3), and virology (4) permit exquisite molecular manipulation of channels. Experiments and theory are wedded with mathematical modeling (1).
Calmodulin – a central Ca2+-sensing molecule in biology – is comprised of two ball-like ends attached by a flexible linker. We have discovered a key rationale for this mysterious bio-architectural design: each ball selectively demodulates different streams of information from a common Ca2+ signal, and then each ball appropriately affects channel function in a distinct way (1- 3). Such features make calmodulin the biological equivalent of a stereo receiver, capable of extracting two channels of information from a common radio signal.
Dick, I.E., Tadross, M.R., Liang, H., Tay, L.H., Yang, W., and Yue, D.T. (2008). A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels. Nature 451:830-834. (see http://www.f1000biology.com/article/id/1102182)
Mori, M.X., Vander Kooi, C.W., Leahy, D.J., and Yue, D.T. (2008). Crystal structure of the CaV2 IQ domain in complex with Ca2+/calmodulin: High-resolution mechanistic implications for channel regulation by Ca2+. Structure 16:607-620 (featured article of the month).
Tadross, M.R., Dick, I.E., and Yue, D.T. (2008). Mechanism of local and global Ca2+ sensing by calmodulin in complex with a Ca2+ channel. Cell 133:1228-1340. (cover article).