Calmodulin supports both inactivation and facilitation of L-type calcium channels.

Published

Journal Article

L-type Ca2+ channels support Ca2+ entry into cells, which triggers cardiac contraction, controls hormone secretion from endocrine cells and initiates transcriptional events that support learning and memory. These channels are examples of molecular signal-transduction units that regulate themselves through their own activity. Among the many types of voltage-gated Ca2+ channel, L-type Ca2+ channels particularly display inactivation and facilitation, both of which are closely linked to the earlier entry of Ca2+ ions. Both forms of autoregulation have a significant impact on the amount of Ca2+ that enters the cell during repetitive activity, with major consequences downstream. Despite extensive biophysical analysis, the molecular basis of autoregulation remains unclear, although a putative Ca2+-binding EF-hand motif and a nearby consensus calmodulin-binding isoleucine-glutamine ('IQ') motif in the carboxy terminus of the alpha1C channel subunit have been implicated. Here we show that calmodulin is a critical Ca2+ sensor for both inactivation and facilitation, and that the nature of the modulatory effect depends on residues within the IQ motif important for calmodulin binding. Replacement of the native isoleucine by alanine removed Ca2+-dependent inactivation and unmasked a strong facilitation; conversion of the same residue to glutamate eliminated both forms of autoregulation. These results indicate that the same calmodulin molecule may act as a Ca2+ sensor for both positive and negative modulation.

Full Text

Duke Authors

Cited Authors

  • Zühlke, RD; Pitt, GS; Deisseroth, K; Tsien, RW; Reuter, H

Published Date

  • May 13, 1999

Published In

Volume / Issue

  • 399 / 6732

Start / End Page

  • 159 - 162

PubMed ID

  • 10335846

Pubmed Central ID

  • 10335846

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/20200

Language

  • eng

Conference Location

  • England