Molecular determinants of magnesium-dependent synaptic plasticity at electrical synapses formed by connexin36

Nat Commun. 2014 Aug 19;5:4667. doi: 10.1038/ncomms5667.


Neuronal gap junction (GJ) channels composed of connexin36 (Cx36) play an important role in neuronal synchronization and network dynamics. Here we show that Cx36-containing electrical synapses between inhibitory neurons of the thalamic reticular nucleus are bidirectionally modulated by changes in intracellular free magnesium concentration ([Mg(2+)]i). Chimeragenesis demonstrates that the first extracellular loop of Cx36 contains a Mg(2+)-sensitive domain, and site-directed mutagenesis shows that the pore-lining residue D47 is critical in determining high Mg(2+)-sensitivity. Single-channel analysis of Mg(2+)-sensitive chimeras and mutants reveals that [Mg(2+)]i controls the strength of electrical coupling mostly via gating mechanisms. In addition, asymmetric transjunctional [Mg(2+)]i induces strong instantaneous rectification, providing a novel mechanism for electrical rectification in homotypic Cx36 GJs. We suggest that Mg(2+)-dependent synaptic plasticity of Cx36-containing electrical synapses could underlie neuronal circuit reconfiguration via changes in brain energy metabolism that affects neuronal levels of intracellular ATP and [Mg(2+)]i.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / physiology
  • Animals
  • Antigens / physiology
  • Connexin 43 / physiology
  • Connexins / chemistry*
  • Connexins / physiology*
  • Electrical Synapses / physiology*
  • Energy Metabolism / physiology
  • Female
  • Magnesium / physiology*
  • Male
  • Mice
  • Models, Animal
  • Neuronal Plasticity / physiology*
  • Neurons / physiology
  • Thalamic Nuclei / physiology*


  • Antigens
  • Connexin 43
  • Connexins
  • D47 antigen
  • connexin 36
  • Adenosine Triphosphate
  • Magnesium