Regulation of muscarinic receptor function in developing oligodendrocytes by agonist exposure

Authors


nstituto Cajal (CSIC), Avenida Doctor Arce 37, 28002 Madrid, Spain. E-mail: galmazan@pharma.mcgill.ca

Abstract

  • Oligodendrocytes, the myelin forming cells in the CNS, express muscarinic acetylcholine receptors (mAChR), primarily M3, coupled to various signal transduction pathways.

  • In the present study we have investigated whether mAChR undergo functional agonist-induced regulation in cultured oligodendrocyte progenitors and differentiated oligodendrocytes.

  • The muscarinic agonist, carbachol (CCh) caused a time-dependent desensitization of phosphoinositide (PI) hydrolysis, and the internalization and down-regulation of receptors. Short-time desensitization (5 min) of PI hydrolysis occurred without receptor internalization and reached 54% by 1 h. The same treatment decreased cell surface receptors labelled with the non-permeable ligand [3H]-NMS by 47%, while total receptor density ([3H]-scopolamine binding) decreased by 30%. Longer CCh treatment down-regulated receptors by 70% and desensitized the PI response by 80%.

  • Although protein kinase C (PKC) activation desensitized mAChR, CCh-mediated desensitization was independent of PKC.

  • Inhibition of receptor endocytosis by low temperature during the pre-stimulation period or in the presence of hyperosmotic sucrose (0.5 M) blocked desensitization, receptor internalization and down-regulation.

  • Recovery of surface mAChR and their functional activity following down-regulation was slow, returning to control levels by 24 h after agonist removal. In progenitor cells, dose-response curves for CCh-mediated PI hydrolysis and c-fos mRNA expression showed that newly synthesized mAChR were supersensitive after recovery.

  • Overall, the present results provide evidence of functional agonist-mediated mAChR regulation in brain oligodendroglial cells.

British Journal of Pharmacology (2003) 138, 47–56. doi:10.1038/sj.bjp.0705002

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