David Yue of Biomedical Engineering
on the promises of calcium:
One of your discoveries was such a boon that you dubbed it “The Rosetta Stone.” Why?
YUE: Yes, we call NSCaTE the Rosetta Stone. The existence and crucial importance of local/global calcium selectivity have been recognized now for nearly a decade, but the underlying mechanism of this selectivity has been elusive. NSCaTE provides a vital and practical clue by which the mechanism could be unlocked, much as the Rosetta Stone ultimately enabled translation of Egyptian hieroglyphics.
You’ve likened your recent research on calcium signals to a trilogy with the first advance being the discovery of NSCaTE. What are the second and third parts?
YUE: The second advance uses novel experimental means to control calcium concentrations within nanometers of channels, and thereby uncovers a deep mechanism of spatial calcium selectivity, as conveyed by NSCaTE. Stay tuned, this story is coming out soon.
The third result of the trilogy is the atomic resolution of calmodulin in complex with a vital element of neuronal calcium channels. Obtained in collaboration with Daniel Leahy’s group, this structure suggests some unanticipated atomic-level conformational changes that underlie CaM decoding of calcium concentrations. These results provide a molecular-structural context for parts one and two of the trilogy, and was published April 2008 in the journal Structure, with postdoctoral fellow Masayuki Mori as the lead author.
What are some of the future promises of calcium signal research?
YUE: Calcium is one of the main languages of life at the molecular and cellular levels. Understanding how this language is encoded and decoded promises understanding of normal biological function, as well as disease processes. Identifying molecular manipulations that can tune calcium signaling has huge potential for developing therapies for a wide spectrum of diseases. For example, heritable problems in calcium feedback regulation of calcium channels in Timothy Syndrome are implicated in autism, cardiac arrhythmias, and faulty development. How this syndrome arises, and how to ameliorate the consequences of this disease, is intimately related to calcium signal research.
David Yue on how calcium controls everything we do: