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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.
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CRC Press eBookspp.15-34, (2023)
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The Journal of biological chemistry (2021): 100502-100502
bioRxiv (Cold Spring Harbor Laboratory) (2021)
Analysis and Simulation of the Cardiac System — Ischemiapp.421-435, (2020)
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