Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression.

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2016-02-19

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Abstract

Voltage-gated CaV1.2 channels (L-type calcium channel α1C subunits) are critical mediators of transcription-dependent neural plasticity. Whether these channels signal via the influx of calcium ion (Ca(2+)), voltage-dependent conformational change (VΔC), or a combination of the two has thus far been equivocal. We fused CaV1.2 to a ligand-gated Ca(2+)-permeable channel, enabling independent control of localized Ca(2+) and VΔC signals. This revealed an unexpected dual requirement: Ca(2+) must first mobilize actin-bound Ca(2+)/calmodulin-dependent protein kinase II, freeing it for subsequent VΔC-mediated accumulation. Neither signal alone sufficed to activate transcription. Signal order was crucial: Efficiency peaked when Ca(2+) preceded VΔC by 10 to 20 seconds. CaV1.2 VΔC synergistically augmented signaling by N-methyl-d-aspartate receptors. Furthermore, VΔC mistuning correlated with autistic symptoms in Timothy syndrome. Thus, nonionic VΔC signaling is vital to the function of CaV1.2 in synaptic and neuropsychiatric processes.

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10.1126/science.aad3647

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Li, Boxing, Michael R Tadross and Richard W Tsien (2016). Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression. Science, 351(6275). pp. 863–867. 10.1126/science.aad3647 Retrieved from https://hdl.handle.net/10161/15558.

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Tadross

Michael Raphael Tadross

Assistant Professor of Biomedical Engineering

Dr. Tadross' lab develops technologies to rapidly deliver drugs to genetically defined subsets of cells in the brain. By using these reagents in mouse models of neuropsychiatric disease, his group is mapping how specific receptors on defined cells and synapses in the brain give rise to diverse neural computations and behaviors.  The approach leverages drugs currently in use to treat human neuropsychiatric disease, facilitating clinically relevant interpretation of the mapping effort.

He received his B.S. degree in Electrical & Computer Engineering at Rutgers University, an M.D.-Ph.D. degree in Biomedical Engineering at the Johns Hopkins School of Medicine, and completed his postdoctoral study in Cellular Neuroscience at Stanford University. He began his independent research program as a fellow at the HHMI Janelia Research Campus.


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