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Cell
Oct 23, 2014;159 (3): 608-22.

Apocalmodulin itself promotes ion channel opening and Ca(2+) regulation.

Paul J Adams, Manu Ben-Johny, Ivy E Dick, Takanari Inoue, David T Yue
Author Information
  1. Paul J Adams: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience, Center for Cell Dynamics, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
  2. Manu Ben-Johny: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience, Center for Cell Dynamics, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
  3. Ivy E Dick: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience, Center for Cell Dynamics, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
  4. Takanari Inoue: Department of Cell Biology and Center for Cell Dynamics, The Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.
  5. David T Yue: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience, Center for Cell Dynamics, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA. Electronic address: dyue@jhmi.edu.
PMID: 25417111 DOI: 10.1016/j.cell.2014.09.047

Abstract

The Ca(2+)-free form of calmodulin (apoCaM) often appears inert, modulating target molecules only upon conversion to its Ca(2+)-bound form. This schema has appeared to govern voltage-gated Ca(2+) channels, where apoCaM has been considered a dormant Ca(2+) sensor, associated with channels but awaiting the binding of Ca(2+) ions before inhibiting channel opening to provide vital feedback inhibition. Using single-molecule measurements of channels and chemical dimerization to elevate apoCaM, we find that apoCaM binding on its own markedly upregulates opening, rivaling the strongest forms of modulation. Upon Ca(2+) binding to this CaM, inhibition may simply reverse the initial upregulation. As RNA-edited and -spliced channel variants show different affinities for apoCaM, the apoCaM-dependent control mechanisms may underlie the functional diversity of these variants and explain an elongation of neuronal action potentials by apoCaM. More broadly, voltage-gated Na channels adopt this same modulatory principle. ApoCaM thus imparts potent and pervasive ion-channel regulation. PAPERCLIP:

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Grants

  1. R01 MH065531/NIMH NIH HHS
  2. R01 NS073874/NINDS NIH HHS
  3. R01 NS085074/NINDS NIH HHS
  4. R37 HL076795/NHLBI NIH HHS

MeSH Term

Animals
Calcium Channels
Calcium Channels, L-Type
Calmodulin
Electrophysiological Phenomena
Humans
Mice
Rats
Sodium Channels

Chemicals

CACNA1D protein, human
Calcium Channels
Calcium Channels, L-Type
Calmodulin
Sodium Channels
Cacna1d protein, rat
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Article has an altmetric score of 48

Word Cloud

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