The Ca2+-free form of calmodulin (apoCaM) often appears inert, modulating target molecules only upon conversion to its Ca2+-bound form. This schema has appeared to govern voltage-gated Ca2+ channels, where apoCaM has been considered a dormant Ca2+ sensor, associated with channels but awaiting the binding of Ca2+ 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 Ca2+ 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.
Apocalmodulin Itself Promotes Ion Channel Opening and Ca2+ Regulation
Paul J. Adams, Manu Ben-Johny, Ivy E. Dick, Takanari Inoue, David T. Yue
Volume 159, Issue 3, p608–622, 23 October 2014
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