Cell. 2014 Oct 23;159(3):608-22. doi: 10.1016/j.cell.2014.09.047.

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

Adams PJ¹, Ben-Johny M¹, Dick IE¹, Inoue T², Yue DT³.

Author information

1: 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: 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.
3: 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.

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.