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Volume 10Nov 2009

Scientific Report

  • EMBO reports (2009) 10, 873 - 880
  • doi:10.1038/embor.2009.125

Published online: 3 July 2009

The NALCN ion channel is activated by M3 muscarinic receptors in a pancreatic bold beta-cell lineEMBO Open

Leigh Anne Swayne1,2,3, Alexandre Mezghrani1,2,3, Annie Varrault1,2,3, Jean Chemin1,2,3, Gyslaine Bertrand1,2,3, Stephane Dalle1,2,3, Emmanuel Bourinet1,2,3, Philippe Lory1,2,3, Richard J Miller4, Joel Nargeot1,2,3 & Arnaud Monteil1,2,3

  1. Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, 34094 Montpellier, France
  2. Institut National de la Santé et de la Recherche Médicale, Unité 661, 34094 Montpellier, France
  3. Universités Montpellier I & II, 141 Rue de la Cardonille, 34094 Montpellier, France
  4. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, Illinois 60611-3008, USA

Correspondence to:

Arnaud Monteil, Tel: +33 4 99 61 99 36; Fax: +33 4 99 61 99 01; E-mail: arnaud.monteil@igf.cnrs.fr

Received 9 December 2008; Revised 27 April 2009; Accepted 29 April 2009

A previously uncharacterized putative ion channel, NALCN (sodium leak channel, non-selective), has been recently shown to be responsible for the tetrodotoxin (TTX)-resistant sodium leak current implicated in the regulation of neuronal excitability. Here, we show that NALCN encodes a current that is activated by M3 muscarinic receptors (M3R) in a pancreatic beta-cell line. This current is primarily permeant to sodium ions, independent of intracellular calcium stores and G proteins but dependent on Src activation, and resistant to TTX. The current is recapitulated by co-expression of NALCN and M3R in human embryonic kidney-293 cells and in Xenopus oocytes. We also show that NALCN and M3R belong to the same protein complex, involving the intracellular I–II loop of NALCN and the intracellular i3 loop of M3R. Taken together, our data show the molecular basis of a muscarinic-activated inward sodium current that is independent of G-protein activation, and provide new insights into the properties of NALCN channels.

  • Keywords:

    • ion channel,
    • G proteins,
    • M3 muscarinic receptor,
    • NALCN,
    • Src

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