Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Ca(v)1.3 channels.
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Ca(2+)/calmodulin- and voltage-dependent inactivation (CDI and VDI) comprise vital prototypes of Ca(2+) channel modulation, rich with biological consequences. Although the events initiating CDI and VDI are known, their downstream mechanisms have eluded consensus. Competing proposals include hinged-lid occlusion of channels, selectivity filter collapse, and allosteric inhibition of the activation gate. Here, novel theory predicts that perturbations of channel activation should alter inactivation in distinctive ways, depending on which hypothesis holds true. Thus, we systematically mutate the activation gate, formed by all S6 segments within Ca(V)1.3. These channels feature robust baseline CDI, and the resulting mutant library exhibits significant diversity of activation, CDI, and VDI. For CDI, a clear and previously unreported pattern emerges: activation-enhancing mutations proportionately weaken inactivation. This outcome substantiates an allosteric CDI mechanism. For VDI, the data implicate a "hinged lid-shield" mechanism, similar to a hinged-lid process, with a previously unrecognized feature. Namely, we detect a "shield" in Ca(V)1.3 channels that is specialized to repel lid closure. These findings reveal long-sought downstream mechanisms of inactivation and may furnish a framework for the understanding of Ca(2+) channelopathies involving S6 mutations.
Amino Acid Sequence
Calcium Channels, L-Type
Ion Channel Gating
Molecular Sequence Data
Structural Homology, Protein
Published Version (Please cite this version)10.1085/jgp.200910308
Publication InfoTadross, Michael R; Ben Johny, Manu; & Yue, David T (2010). Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Ca(v)1.3 channels. J Gen Physiol, 135(3). pp. 197-215. 10.1085/jgp.200910308. Retrieved from https://hdl.handle.net/10161/15561.
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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.<
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