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Preparation of Rat Oligodendrocyte Progenitor Cultures and Quantification of Oligodendrogenesis Using Dual-infrared Fluorescence Scanning
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Regulation of muscarinic receptor function in developing oligodendrocytes by agonist exposure

Eduardo Molina-Holgado1, Amani Khorchid, Hsueh-Ning Liu

  • 1Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002 Madrid, Spain.

British Journal of Pharmacology
|January 11, 2003
PubMed

Insights

Muscarinic acetylcholine receptors (mAChR) in oligodendrocytes undergo agonist-induced regulation, including desensitization and down-regulation. This process is independent of protein kinase C and involves receptor internalization, with slow recovery and supersensitivity in progenitor cells.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pharmacology

Background:

  • Oligodendrocytes, crucial for CNS myelin, express muscarinic acetylcholine receptors (mAChR), primarily M3 subtypes.
  • These receptors are linked to diverse intracellular signaling cascades.

Purpose of the Study:

  • To investigate the functional regulation of mAChR in response to agonist stimulation in oligodendrocyte progenitor cells and differentiated oligodendrocytes.
  • To elucidate the mechanisms underlying agonist-induced mAChR desensitization, internalization, and down-regulation.

Main Methods:

  • Primary cultures of oligodendrocyte progenitors and differentiated oligodendrocytes were used.
  • Phosphoinositide (PI) hydrolysis assays were performed to measure receptor signaling.
  • Receptor expression was quantified using radioligand binding assays with non-permeable and total receptor ligands.
  • Inhibition of endocytosis was achieved using low temperature and hyperosmotic sucrose.
  • Protein kinase C (PKC) activation and c-fos mRNA expression were assessed.

Main Results:

  • Carbachol (CCh), a muscarinic agonist, induced time-dependent desensitization of PI hydrolysis, receptor internalization, and down-regulation.
  • Short CCh exposure desensitized PI hydrolysis without internalization, while longer exposure led to significant receptor down-regulation (up to 70%).
  • CCh-mediated desensitization was independent of PKC but dependent on receptor endocytosis.
  • Recovery of surface mAChR and function was slow (24 h), with newly synthesized receptors showing supersensitivity in progenitor cells.

Conclusions:

  • Oligodendrocytes exhibit functional agonist-mediated regulation of mAChR.
  • Receptor internalization is a key mechanism in mAChR desensitization and down-regulation.
  • The observed supersensitivity post-recovery suggests adaptive changes in mAChR signaling in oligodendrocytes.

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