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Metabotropic NMDA receptor signaling couples Src family kinases to pannexin-1 during excitotoxicity

Nicholas L Weilinger1,2, Alexander W Lohman1,2, Brooke D Rakai1

  • 1Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

Nature Neuroscience
|February 9, 2016
PubMed

Insights

Neuronal N-methyl-D-aspartate receptors (NMDARs) signal without opening their ion channels, contributing to excitotoxicity. Disrupting the NMDAR-Src-Panx1 complex offers neuroprotection against stroke and ischemia.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cellular Signaling

Background:

  • Neuronal N-methyl-D-aspartate receptors (NMDARs) are crucial for synaptic plasticity but implicated in excitotoxicity and neuronal death.
  • Classical understanding posits NMDARs require co-agonists and membrane depolarization for activation and ion flux.
  • Excitotoxicity, mediated by NMDAR overactivation, is a key pathological mechanism in neurological disorders.

Purpose of the Study:

  • To investigate a novel signaling pathway of NMDARs independent of their ion channel activity.
  • To elucidate the role of the NMDAR-Src-Panx1 complex in excitotoxicity and neuronal injury.
  • To evaluate the neuroprotective potential of targeting this signaling complex in ischemic conditions.

Main Methods:

  • Utilized pharmacological pore blockers (MK-801) and genetic modifications (Ca(2+)-impermeable NMDAR variant) to isolate NMDAR signaling from ion conduction.
  • Investigated the formation and activation of the NMDAR-Src-Panx1 signaling complex, including Panx1 phosphorylation at Y308.
  • Administered an interfering peptide to disrupt the NMDAR-Src-Panx1 complex in vitro and in vivo models of ischemia and stroke.

Main Results:

  • NMDARs were found to signal upon ligand binding even when ion conduction was blocked, leading to excitotoxic effects.
  • The NMDAR-Src-Panx1 complex was identified as a critical mediator of these non-conductive NMDAR signals.
  • Disruption of the NMDAR-Src-Panx1 complex demonstrated significant neuroprotection when applied before or after ischemic events.

Conclusions:

  • NMDARs possess a signaling capacity distinct from their ion channel function, contributing to excitotoxicity.
  • The NMDAR-Src-Panx1 complex represents a novel therapeutic target for neuroprotection.
  • Targeting this pathway offers a promising strategy for mitigating neuronal damage in stroke and other ischemic brain injuries.

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