Molecular Neurobiology

, Volume 56, Issue 12, pp 8345–8363 | Cite as

NMDA Receptors Regulate Neuregulin 2 Binding to ER-PM Junctions and Ectodomain Release

  • Detlef Vullhorst
  • Andres BuonannoEmail author


Unprocessed pro-neuregulin 2 (pro-NRG2) accumulates on neuronal cell bodies at junctions between the endoplasmic reticulum and plasma membrane (ER-PM junctions). NMDA receptors (NMDARs) trigger NRG2 ectodomain shedding from these sites followed by activation of ErbB4 receptor tyrosine kinases, and ErbB4 signaling cell-autonomously downregulates intrinsic excitability of GABAergic interneurons by reducing voltage-gated sodium channel currents. NMDARs also promote dispersal of Kv2.1 clusters from ER-PM junctions and cause a hyperpolarizing shift in its voltage-dependent channel activation, suggesting that NRG2/ErbB4 and Kv2.1 work together to regulate intrinsic interneuron excitability in an activity-dependent manner. Here we explored the cellular processes underlying NMDAR-dependent NRG2 shedding in cultured rat hippocampal neurons. We report that NMDARs control shedding by two separate but converging mechanisms. First, NMDA treatment disrupts binding of pro-NRG2 to ER-PM junctions by post-translationally modifying conserved Ser/Thr residues in its intracellular domain. Second, using a mutant NRG2 protein that cannot be modified at these residues and that fails to accumulate at ER-PM junctions, we demonstrate that NMDARs also directly promote NRG2 shedding by ADAM-type metalloproteinases. Using pharmacological and shRNA-mediated knockdown, and metalloproteinase overexpression, we unexpectedly find that ADAM10, but not ADAM17/TACE, is the major NRG2 sheddase acting downstream of NMDAR activation. Together, these findings reveal how NMDARs exert tight control over the NRG2/ErbB4 signaling pathway, and suggest that NRG2 and Kv2.1 are co-regulated components of a shared pathway that responds to elevated extracellular glutamate levels.


Neuregulin Kv2.1 ADAM10 ER-PM junction Sheddase Activity-dependent 



We are grateful to Kate McDaniel for help with cloning ADAM10 and ADAM17 constructs, and Drs. Vincent Schram and Carolyn Smith from the Porter Neuroscience Center imaging core for expert assistance with confocal microscopy.

Funding Information

This work was supported by the intramural research program of the Eunice Kennedy Shriver Institute of Child Health and Human Development (NICHD; ZIA-HD000711).

Compliance with Ethical Standards

Animals were treated in accordance with NIH Animal Welfare guidelines. All procedures were approved by the NICHD Animal Care and User Committee.

Supplementary material

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© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Section on Molecular NeurobiologyEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaUSA

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