Decoding calcium at a calcium cocktail party--How calmodulin listens as it regulates calcium channels |
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| Air date: | Monday, October 20, 2008, 12:00:00 PM |
| Category: | Neuroscience |
| Runtime: | 75 minutes |
| NLM Title: | Decoding calcium at a calcium cocktail party--How calmodulin listens as it regulates calcium channels [electronic resource] / David Yue. |
| Series: | NIH neuroscience seminar series |
| Author: | Yue, David. National Institutes of Health (U.S.) |
| Publisher: | [Bethesda, Md. : National Institutes of Health, 2008] |
| Other Title(s): | NIH neuroscience seminar series |
| Abstract: | (CIT): 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 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+ 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 and a biological fluorescence technique called FRET. The latter approach offers a dynamic readout of molecular motions in single living cells. Molecular biology, biochemistry, and virology permit exquisite molecular manipulation of channels. Experiments and theory are wedded with mathematical modeling. 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. 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. |
| Subjects: | Calcium Channels--physiology Calcium Signaling--physiology Calmodulin--physiology |
| Publication Types: | Government Publications Lectures |
| Download: | Download
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| NLM Classification: | QU 55.2 |
| NLM ID: | 101488640 |
| CIT File ID: | 14710 |
| CIT Live ID: | 7124 |
| Permanent link: | http://videocast.nih.gov/launch.asp?14710 |
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Enhanced Audio Podcast | 1:14:56 |
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Enhanced Video Podcast | 1:14:56 | |