TY - JOUR
T1 - Molecular determinants of magnesium-dependent synaptic plasticity at electrical synapses formed by connexin36
AU - Palacios-Prado, Nicolás
AU - Chapuis, Sandrine
AU - Panjkovich, Alejandro
AU - Fregeac, Julien
AU - Nagy, James I.
AU - Bukauskas, Feliksas F.
N1 - Funding Information:
We thank Michael V.L. Bennett, Vytautas K. Verselis and Thaddeus A. Bargiello for helpful comments and discussions. We thank Nerijus Paulauskas for assistance with S4SM, and Angele Bukauskiene and Alis Dicpinigaitis for excellent technical assistance. We thank Jim McIlvain and Elizabeth Dille from Zeiss for assistance with confocal imaging. Nicolás Palacios-Prado is a Howard Hughes Medical Institute International Student Research Fellow. This work was supported by the Grass Foundation with a Grass Fellowship to N.P-P., by a grant from the Canadian Institute of Health Research to J.I.N. and by the National Institute of Health grant R01NS 072238 to F.F.B.
PY - 2014/8/19
Y1 - 2014/8/19
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms5667
DO - 10.1038/ncomms5667
M3 - Article
AN - SCOPUS:84907362937
VL - 5
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 4667
ER -