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

EMBO Rep. 2009 Aug;10(8):873-80. doi: 10.1038/embor.2009.125. Epub 2009 Jul 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line
  • Electrophysiology
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Patch-Clamp Techniques
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • RNA Interference
  • RNA, Small Interfering
  • Receptor, Muscarinic M3 / genetics
  • Receptor, Muscarinic M3 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction


  • 4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine
  • Enzyme Inhibitors
  • Ion Channels
  • Pyrazoles
  • Pyrimidines
  • RNA, Small Interfering
  • Receptor, Muscarinic M3