JHU biomedical engineering primary faculty
David T. Yue, MD, PhD
Professor of Biomedical Engineering and Neuroscience
Co-Director, Ph.D. Program
Lab: Calcium Signals Laboratory
We are deeply saddened to share with our community the news of David Yue’s passing on Tuesday, December 23, 2014. David was an extraordinary man who touched so many. Our thoughts and prayers are with David’s family, and all those who feel his loss. Learn more.
Elliot McVeigh, PhD
Massey Professor and Director
Johns Hopkins Department of Biomedical Engineering
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.
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).