Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels

Jacqueline Niu, Ivy E. Dick, Wanjun Yang, Moradeke A. Bamgboye, David T. Yue, Gordon F. Tomaselli, Takanari Inoue, Manu Ben-Johny

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Calmodulin (CaM) serves as a pervasive regulatory subunit of CaV1, CaV2, and NaV1 channels, exploiting a functionally conserved carboxy-tail element to afford dynamic Ca2+-feedback of cellular excitability in neurons and cardiomyocytes. Yet this modularity counters functional adaptability, as global changes in ambient CaM indiscriminately alter its targets. Here, we demonstrate that two structurally unrelated proteins, SH3 and cysteine-rich domain (stac) and fibroblast growth factor homologous factors (fhf) selectively diminish Ca2+/CaM-regulation of CaV1 and NaV1 families, respectively. The two proteins operate on allosteric sites within upstream portions of respective channel carboxy-tails, distinct from the CaM-binding interface. Generalizing this mechanism, insertion of a short RxxK binding motif into CaV1.3 carboxy-tail confers synthetic switching of CaM regulation by Mona SH3 domain. Overall, our findings identify a general class of auxiliary proteins that modify Ca2+/CaM signaling to individual targets allowing spatial and temporal orchestration of feedback, and outline strategies for engineering Ca2+/CaM signaling to individual targets.

Original languageEnglish (US)
JournaleLife
Volume7
DOIs
StatePublished - Sep 10 2018
Externally publishedYes

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Keywords

  • Ca channels
  • calcium regulation
  • calmodulin
  • fibroblast growth factor homologous factors
  • molecular biophysics
  • Na channels
  • SH3 and cysteine rich domain proteins
  • structural biology

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Niu, J., Dick, I. E., Yang, W., Bamgboye, M. A., Yue, D. T., Tomaselli, G. F., Inoue, T., & Ben-Johny, M. (2018). Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels. eLife, 7. https://doi.org/10.7554/eLife.35222