A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels.
Abstract
Ca2+/calmodulin-dependent regulation of voltage-gated CaV1-2 Ca2+ channels shows extraordinary
modes of spatial Ca2+ decoding and channel modulation, vital for many biological functions.
A single calmodulin (CaM) molecule associates constitutively with the channel's carboxy-terminal
tail, and Ca2+ binding to the C-terminal and N-terminal lobes of CaM can each induce
distinct channel regulations. As expected from close channel proximity, the C-lobe
responds to the roughly 100-microM Ca2+ pulses driven by the associated channel, a
behaviour defined as 'local Ca2+ selectivity'. Conversely, all previous observations
have indicated that the N-lobe somehow senses the far weaker signals from distant
Ca2+ sources. This 'global Ca2+ selectivity' satisfies a general signalling requirement,
enabling a resident molecule to remotely sense cellular Ca2+ activity, which would
otherwise be overshadowed by Ca2+ entry through the host channel. Here we show that
the spatial Ca2+ selectivity of N-lobe CaM regulation is not invariably global but
can be switched by a novel Ca2+/CaM-binding site within the amino terminus of channels
(NSCaTE, for N-terminal spatial Ca2+ transforming element). Native CaV2.2 channels
lack this element and show N-lobe regulation with a global selectivity. On the introduction
of NSCaTE into these channels, spatial Ca2+ selectivity transforms from a global to
local profile. Given this effect, we examined CaV1.2/CaV1.3 channels, which naturally
contain NSCaTE, and found that their N-lobe selectivity is indeed local. Disruption
of this element produces a global selectivity, confirming the native function of NSCaTE.
Thus, differences in spatial selectivity between advanced CaV1 and CaV2 channel isoforms
are explained by the presence or absence of NSCaTE. Beyond functional effects, the
position of NSCaTE on the channel's amino terminus indicates that CaM can bridge the
amino terminus and carboxy terminus of channels. Finally, the modularity of NSCaTE
offers practical means for understanding the basis of global Ca2+ selectivity.
Type
Journal articleSubject
Amino Acid SequenceAnimals
Calcium
Calcium Channels
Calcium Signaling
Calmodulin
Cell Line
Evolution, Molecular
Humans
Molecular Sequence Data
Substrate Specificity
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https://hdl.handle.net/10161/15555Published Version (Please cite this version)
10.1038/nature06529Publication Info
Dick, Ivy E; Tadross, Michael R; Liang, Haoya; Tay, Lai Hock; Yang, Wanjun; & Yue,
David T (2008). A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV
channels. Nature, 451(7180). pp. 830-834. 10.1038/nature06529. Retrieved from https://hdl.handle.net/10161/15555.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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