David T. Yue, M.D., Ph.D.
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 work thus focuses on the “transistors” of Ca2+ signaling?voltage-gated Ca2+ channels. Unmasking their secrets critically deepen understanding of normal biology, and promise to reveal new therapies for disease.
What tools do we use? 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 (1-5) and a biological fluorescence technique called FRET (3,5). The latter approach offers a dynamic readout of molecular motions in single living cells. Molecular biology (1-5), biochemistry (1,2,4), and virology (4) permit exquisite molecular manipulation of channels. Experiments and theory are wedded with mathematical modeling (4).
What’s an example of our discovery? Calmodulin (CaM)?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 CaM the biological equivalent of a stereo receiver, capable of extracting two channels of information from a common radio signal. Using viral gene transfer in adult heart cells, we found that CaM-mediated feedback on cardiac L-type Ca2+ channels is the dominant control factor in controlling the cardiac action potential duration (4), a vital excitability parameter whose prolongation in heart failure and long QT syndromes precipitates life-threatening arrhythmias. Our understanding of CaM regulation of Ca2+ channels enabled us to genetically engineer a novel biosensor showing marked enrichment of CaM in the nanodomain of individuals channels (5).
- *Peterson, B.Z., *DeMaria, C.D., and Yue, D.T. 1999. Calmodulin is the calcium sensor for calcium-dependent inactivation of L-type calcium channels. Neuron 22:549-558. *co-first authors.
- DeMaria, C.D., Soong, T.W., Alseikhan, B.A., Alvania, R.S., and Yue, D.T. 2001. Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels. Nature 411:484-489.
- Liang, H., DeMaria, C.D., Erickson, M.G., Mori, M.X., Alseikhan, B.A., and Yue, D.T. 2003. Unified mechanisms of Ca2+ regulation across the Ca2+ channel family. Neuron 39:951-960.
- Erickson, M.G., Alseikhan, B.A., Peterson, B.Z., and Yue, D.T. 2001. Preassociation of calmodulin with voltage-gated Ca2+ channels revealed by FRET in single living cells. Neuron 31:973-985
- Erickson, M.G., Liang, H., Mori, M.X., and Yue, D.T. 2003.
- FRET two-hybrid mapping reveals function and location of L-type Ca2+ channel CaM preassociation. Neuron 39:97-107.
- Alseikhan, B.A., DeMaria, C.D., Colecraft, H.M., and Yue, D.T. 2002. Engineered calmodulins reveal unexpected eminence of Ca channel inactivation in controlling heart excitation. Proc. Natl. Acad. Sci. U.S.A. 99:17185-17190.
- Mori, M.X., Erickson, M.G., and Yue, D.T. (2004). Functional stoichiometry and local enrichment of calmodulin interacting with Ca2+ channels. Science 304:432-435. (see Perspectives in Science 304:394-5; Highlights in Nature Reviews Neuroscience 5:432).