Calmodulin bifurcates the local Ca 2+ signal that modulates P/Q-type Ca 2+ channels

Carla D. Demaria, Tuck Wah Soong, Badr A. Alseikhan, Rebecca S. Alvania, David T. Yue

Research output: Contribution to journalArticle

Abstract

Acute modulation of P/Q-type (α 1A) calcium channels by neuronal activity-dependent changes in intracellular Ca 2+ concentration may contribute to short-term synaptic plasticity, potentially enriching the neurocomputational capabilities of the brain. An unconventional mechanism for such channel modulation has been proposed in which calmodulin (CaM) may exert two opposing effects on individual channels, initially promoting ('facilitation') and then inhibiting ('inactivation') channel opening. Here we report that such dual regulation arises from surprising Ca 2+ -transduction capabilities of CaM. First, although facilitation and inactivation are two competing processes, both require Ca 2+ -CaM binding to a single 'IQ-like' domain on the carboxy tail of α 1A; a previously identified 'CBD' CaM-binding site has no detectable role. Second, expression of a CaM mutant with impairment of all four of its Ca 2+ -binding sites (CaM 1234) eliminates both forms of modulation. This result confirms that CaM is the Ca 2+ sensor for channel regulation, and indicates that CaM may associate with the channel even before local Ca 2+ concentration rises. Finally, the bifunctional capability of CaM arises from bifurcation of Ca 2+ signalling by the lobes of CaM: Ca 2+ binding to the amino-terminal lobe selectively initiates channel inactivation, whereas Ca 2+ sensing by the carboxy-terminal lobe induces facilitation. Such lobe-specific detection provides a compact means to decode local Ca 2+ signals in two ways, and to separately initiate distinct actions on a single molecular complex.

Original languageEnglish (US)
Pages (from-to)484-489
Number of pages6
JournalNature
Volume411
Issue number6836
DOIs
StatePublished - May 24 2001

ASJC Scopus subject areas

  • General

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    Demaria, C. D., Soong, T. W., Alseikhan, B. A., Alvania, R. S., & Yue, D. T. (2001). Calmodulin bifurcates the local Ca 2+ signal that modulates P/Q-type Ca 2+ channels. Nature, 411(6836), 484-489. https://doi.org/10.1038/35078091