Bilobal architecture is a requirement for calmodulin signaling to CaV1.3 channels

Rahul Banerjee, Jesse B. Yoder, David T. Yue, L. Mario Amzel, Gordon F. Tomaselli, Sandra B. Gabelli, Manu Ben-Johny

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Calmodulin (CaM) regulation of voltage-gated calcium (CaV) channels is a powerful Ca2+ feedback mechanism that adjusts Ca2+ influx, affording rich mechanistic insights into Ca2+ decoding. CaM possesses a dual-lobed architecture, a salient feature of the myriad Ca2+-sensing proteins, where two homologous lobes that recognize similar targets hint at redundant signaling mechanisms. Here, by tethering CaM lobes, we demonstrate that bilobal architecture is obligatory for signaling to CaV channels. With one lobe bound, CaV carboxy tail rearranges itself, resulting in a preinhibited configuration precluded from Ca2+ feedback. Reconstitution of two lobes, even as separate molecules, relieves preinhibition and restores Ca2+ feedback. CaV channels thus detect the coincident binding of two Ca2+-free lobes to promote channel opening, a molecular implementation of a logical NOR operation that processes spatiotemporal Ca2+ signals bifurcated by CaM lobes. Overall, a unified scheme of CaV channel regulation by CaM now emerges, and our findings highlight the versatility of CaM to perform exquisite Ca2+ computations.

Original languageEnglish (US)
Pages (from-to)E3026-E3035
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number13
DOIs
StatePublished - Mar 27 2018
Externally publishedYes

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Keywords

  • Ca1.3
  • Calcium regulation
  • Calmodulin
  • Ion channels
  • Voltage-gated Ca channels

ASJC Scopus subject areas

  • General

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