Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Ca(v)1.3 channels.
Abstract
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.
Type
Journal articleSubject
AlgorithmsAmino Acid Sequence
Animals
Calcium Channels
Calcium Channels, L-Type
Calcium Signaling
Calmodulin
Ion Channel Gating
Membrane Potentials
Models, Structural
Molecular Sequence Data
Point Mutation
Protein Conformation
Rats
Signal Transduction
Structural Homology, Protein
Structure-Activity Relationship
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https://hdl.handle.net/10161/15561Published Version (Please cite this version)
10.1085/jgp.200910308Publication Info
Tadross, 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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
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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