α7 Nicotinic Acetylcholine Receptors May Improve Schwann Cell Regenerating Potential via Metabotropic Signaling Pathways

Elisabetta Botticelli; Claudia Guerriero; Sergio Fucile; Maria Egle De Stefano; Carlo Matera; Clelia Dallanoce; Marco De Amici; Ada Maria Tata

doi:10.3390/cells12111494

α7 Nicotinic Acetylcholine Receptors May Improve Schwann Cell Regenerating Potential via Metabotropic Signaling Pathways

Cells. 2023 May 28;12(11):1494. doi: 10.3390/cells12111494.

Authors

Elisabetta Botticelli¹, Claudia Guerriero¹, Sergio Fucile^{2

3}, Maria Egle De Stefano^{1

4}, Carlo Matera⁵, Clelia Dallanoce⁵, Marco De Amici⁵, Ada Maria Tata^{1

4}

Affiliations

¹ Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy.
² IRCCS Neuromed, 86077 Pozzilli, Italy.
³ Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, 00185 Rome, Italy.
⁴ Research Centre of Neurobiology "Daniel Bovet", Sapienza University of Rome, 00185 Rome, Italy.
⁵ Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy.

Abstract

Background: Schwann cells (SCs) are glial cells involved in peripheral axon myelination. SCs also play a strategic role after peripheral nerve injury, regulating local inflammation and axon regeneration. Our previous studies demonstrated the presence of cholinergic receptors in SCs. In particular, the α7 nicotinic acetylcholine receptors (nAChRs) are expressed in SCs after peripheral axotomy, suggesting their involvement in the regulation of SC-regenerating properties. To clarify the role that α7 nAChRs may play after peripheral axon damage, in this study we investigated the signal transduction pathways triggered by receptor activation and the effects produced by their activation.

Methods: Both ionotropic and metabotropic cholinergic signaling were analyzed by calcium imaging and Western blot analysis, respectively, following α7 nAChR activation. In addition, the expression of c-Jun and α7 nAChRs was evaluated by immunocytochemistry and Western blot analysis. Finally, the cell migration was studied by a wound healing assay.

Results: Activation of α7 nAChRs, activated by the selective partial agonist ICH3, did not induce calcium mobilization but positively modulated the PI3K/AKT/mTORC1 axis. Activation of the mTORC1 complex was also supported by the up-regulated expression of its specific p-p70 S6K^Thr389 target. Moreover, up-regulation of p-AMPK^Thr172, a negative regulator of myelination, was also observed concomitantly to an increased nuclear accumulation of the transcription factor c-Jun. Cell migration and morphology analyses proved that α7 nAChR activation also promotes SC migration.

Conclusions: Our data demonstrate that α7 nAChRs, expressed by SCs only after peripheral axon damage and/or in an inflammatory microenvironment, contribute to improve the SCs regenerating properties. Indeed, α7 nAChR stimulation leads to an upregulation of c-Jun expression and promotes Schwann cell migration by non-canonical pathways involving the mTORC1 activity.

Keywords: Schwann cells; cell migration; mTORC1; metabotropic signals; α7 nicotinic receptors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Axons* / metabolism
Calcium / metabolism
Mechanistic Target of Rapamycin Complex 1 / metabolism
Nerve Regeneration
Phosphatidylinositol 3-Kinases / metabolism
Schwann Cells / metabolism
Signal Transduction / physiology
alpha7 Nicotinic Acetylcholine Receptor* / metabolism

Substances

alpha7 Nicotinic Acetylcholine Receptor
Calcium
Phosphatidylinositol 3-Kinases
Mechanistic Target of Rapamycin Complex 1

Grants and funding

This research received no external funding.