Systematic mapping of the state dependence of voltage- and Ca2+-dependent inactivation using simple open-channel measurements.
Abstract
The state from which channel inactivation occurs is both biologically and mechanistically
critical. For example, preferential closed-state inactivation is potentiated in certain
Ca(2+) channel splice variants, yielding an enhancement of inactivation during action
potential trains, which has important consequences for short-term synaptic plasticity.
Mechanistically, the structural substrates of inactivation are now being resolved,
yielding a growing library of molecular snapshots, ripe for functional interpretation.
For these reasons, there is an increasing need for experimentally direct and systematic
means of determining the states from which inactivation proceeds. Although many approaches
have been devised, most rely upon numerical models that require detailed knowledge
of channel-state topology and gating parameters. Moreover, prior strategies have only
addressed voltage-dependent forms of inactivation (VDI), and have not been readily
applicable to Ca(2+)-dependent inactivation (CDI), a vital form of regulation in numerous
contexts. Here, we devise a simple yet systematic approach, applicable to both VDI
and CDI, for semiquantitative mapping of the states from which inactivation occurs,
based only on open-channel measurements. The method is relatively insensitive to the
specifics of channel gating and does not require detailed knowledge of state topology
or gating parameters. Rather than numerical models, we derive analytic equations that
permit determination of the states from which inactivation occurs, based on direct
manipulation of data. We apply this methodology to both VDI and CDI of Ca(V)1.3 Ca(2+)
channels. VDI is found to proceed almost exclusively from the open state. CDI proceeds
equally from the open and nearby closed states, but is disfavored from deep closed
states distant from the open conformation. In all, these outcomes substantiate and
enrich conclusions of our companion paper in this issue (Tadross et al. 2010. J. Gen.
Physiol. doi:10.1085/jgp.200910308) that deduces endpoint mechanisms of VDI and CDI
in Ca(V)1.3. More broadly, the methods introduced herein can be readily generalized
for the analysis of other channel types.
Type
Journal articleSubject
AlgorithmsCalcium Channels
Cell Line
Humans
Ion Channel Gating
Kidney
Membrane Potentials
Models, Biological
Signal Transduction
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https://hdl.handle.net/10161/15560Published Version (Please cite this version)
10.1085/jgp.200910309Publication Info
Tadross, Michael R; & Yue, David T (2010). Systematic mapping of the state dependence of voltage- and Ca2+-dependent inactivation
using simple open-channel measurements. J Gen Physiol, 135(3). pp. 217-227. 10.1085/jgp.200910309. Retrieved from https://hdl.handle.net/10161/15560.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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