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Microglial α7-Nicotinic Acetylcholine Receptors Are Expressed in Mitochondria Rather Than on the Plasma Membrane:

Yoki Nakamura1, Riku Matsuda1, Shogo Kuribayashi1

  • 1Department of Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Journal of Neurochemistry
|June 26, 2025
PubMed

Insights

Microglial alpha7-nicotinic acetylcholine receptors (α7-nAChR) are primarily located in mitochondria, not the cell membrane. This intracellular localization suggests a novel role in regulating mitochondrial function and ATP production in the central nervous system.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pharmacology

Background:

  • Microglia play crucial roles in central nervous system (CNS) immunity and function.
  • The alpha7-nicotinic acetylcholine receptor (α7-nAChR) is implicated in various CNS processes, but its precise role and localization in microglia remain unclear.
  • Chaperones like NACHO and RIC3 are essential for the cell surface expression of α7-nAChR as an ionotropic receptor.

Purpose of the Study:

  • To investigate the subcellular localization and cellular functions of the microglial α7-nAChR.
  • To determine if α7-nAChR in microglia functions as a ligand-gated ion channel.
  • To elucidate the novel roles of microglial α7-nAChR in cellular processes.

Main Methods:

  • Fluorescence-activated cell sorting (FACS) to isolate mouse brain microglia.
  • Quantitative PCR to assess mRNA levels of α7-nAChR, NACHO, and RIC3.
  • Immunofluorescence staining and cell imaging to determine receptor localization.
  • Treatment with α7-nAChR agonist (choline) and antagonist (methyllycaconitine) to assess functional responses.
  • Measurement of intracellular calcium and ATP levels.

Main Results:

  • Microglia express α7-nAChR mRNA, but low levels of NACHO and RIC3 mRNA, suggesting limited cell surface expression.
  • α7-nAChR was predominantly localized intracellularly, particularly within mitochondria, rather than at the plasma membrane.
  • Activation of microglial α7-nAChR with choline did not increase intracellular calcium but significantly elevated intracellular ATP levels.
  • The choline-induced increase in ATP was attenuated by the α7-nAChR antagonist methyllycaconitine.
  • These findings indicate a non-canonical function of α7-nAChR in regulating mitochondrial activity.

Conclusions:

  • Microglial α7-nAChR is primarily localized in mitochondria, mediating a novel function in regulating mitochondrial ATP production.
  • The limited expression of essential chaperones (NACHO, RIC3) contributes to the intracellular sequestration of α7-nAChR.
  • This discovery expands the understanding of α7-nAChR's diverse roles in the CNS and highlights its potential as a therapeutic target for microglia-related neurological disorders.
Keywords:
ATPNACHOmicrogliamitochondriaα7‐nicotinic acetylcholine receptor

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