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 (6) underlying our very thoughts. Moreover, longer-term changes in [Ca2+] control gene expression in neurons. 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+ signalingævoltage-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 (1-6) and a biological fluorescence technique called FRET (4). The latter approach offers a dynamic readout of molecular motions in single living cells. Molecular biology (1-5), biochemistry (1,3,4), and virology (5) permit exquisite molecular manipulation of channels. Experiments and theory are wedded with mathematical modeling (2,5).

     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 (1-4). 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, a vital excitability parameter whose prolongation in heart failure and long QT syndromes precipitates life-threatening arrhythmias. The latter results furnish insight into therapeutic approaches for cardiac arrhythmias in abnormal QT conditions, such as drugs modulating CaM/L-type channel interactions and gene therapy with engineered CaMs.