A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels.

Loading...
Thumbnail Image

Date

2008-02-14

Journal Title

Journal ISSN

Volume Title

Repository Usage Stats

137
views
312
downloads

Citation Stats

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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1038/nature06529

Publication Info

Dick, Ivy E, Michael R Tadross, Haoya Liang, Lai Hock Tay, Wanjun Yang and David T Yue (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.

Scholars@Duke

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.


Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.