Existence of muscarinic acetylcholine receptor (mAChR) and fibroblast growth factor receptor (FGFR) heteroreceptor complexes and their enhancement of neurite outgrowth in neural hippocampal cultures

Giuseppa Mudo', Natale Belluardo, Valentina Di Liberto, Dasiel O. Borroto-Escuela, Fuxe, Monica Frinchi

Risultato della ricerca: Article

18 Citazioni (Scopus)

Abstract

Background Recently, it was demonstrated that G-protein-coupled receptors (GPCRs) can transactivate tyrosine kinase receptors in absence of their ligands. In this work, driven by the observation that mAChRs and fibroblast growth factor receptors (FGFRs) share signalling pathways and regulation of brain functions, it was decided to explore whether mAChRs activation may transactivate FGFRs and, if so, to characterize the related trophic effects in cultured hippocampal neurons. Methods Oxotremorine-M transactivation of FGFRs and related trophic effects were tested in primary hippocampal neurons. Western blotting and in situ proximity ligation assay (PLA) were used to detect FGFR phosphorylation (pFGFR) levels and M1R-FGFR1 heteroreceptor complexes, respectively. Results Oxotremorine-M, a non-selective mAChRs agonist, was able to transactivate FGFR and this transactivation was blocked by Src inhibitors. Oxotremorine-M treatment produced a significant increase in the primary neurite outgrowth that was blocked by pre-treatment with the pFGFR inhibitor SU5402 and Src inhibitors. This trophic effect was almost similar to that induced by fibroblast growth factor-2 (FGF-2). By using atropine as nonselective mAChRs or pirenzepine as selective antagonist for M1receptor (M1R) we could show that mAChRs are involved in modulating the pFGFRs. Using PLA, M1R-FGFR1 heteroreceptor complexes were identified in the hippocampus and cerebral cortex. Conclusion The current findings, by showing functional mAChR-FGFR interactions, will contribute to advance the understanding of the mechanisms involved in the actions of cholinergic drugs on neuronal plasticity. General significant Data may help to develop novel therapeutic strategies not only for neurodegenerative diseases but also for depression-induced atrophy of hippocampal neurons.
Lingua originaleEnglish
pagine (da-a)235-245
Numero di pagine11
RivistaBIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume1861
Stato di pubblicazionePublished - 2017

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Fibroblast Growth Factor Receptors
Muscarinic Receptors
Neurons
Transcriptional Activation
Ligation
Assays
Neurodegenerative diseases
Pirenzepine
Phosphorylation
Neuronal Plasticity
Receptor Protein-Tyrosine Kinases
Fibroblast Growth Factor 2
G-Protein-Coupled Receptors
Atropine
Neurodegenerative Diseases
Cerebral Cortex
Cholinergic Agents
Atrophy
Plasticity
Neuronal Outgrowth

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology

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title = "Existence of muscarinic acetylcholine receptor (mAChR) and fibroblast growth factor receptor (FGFR) heteroreceptor complexes and their enhancement of neurite outgrowth in neural hippocampal cultures",
abstract = "Background Recently, it was demonstrated that G-protein-coupled receptors (GPCRs) can transactivate tyrosine kinase receptors in absence of their ligands. In this work, driven by the observation that mAChRs and fibroblast growth factor receptors (FGFRs) share signalling pathways and regulation of brain functions, it was decided to explore whether mAChRs activation may transactivate FGFRs and, if so, to characterize the related trophic effects in cultured hippocampal neurons. Methods Oxotremorine-M transactivation of FGFRs and related trophic effects were tested in primary hippocampal neurons. Western blotting and in situ proximity ligation assay (PLA) were used to detect FGFR phosphorylation (pFGFR) levels and M1R-FGFR1 heteroreceptor complexes, respectively. Results Oxotremorine-M, a non-selective mAChRs agonist, was able to transactivate FGFR and this transactivation was blocked by Src inhibitors. Oxotremorine-M treatment produced a significant increase in the primary neurite outgrowth that was blocked by pre-treatment with the pFGFR inhibitor SU5402 and Src inhibitors. This trophic effect was almost similar to that induced by fibroblast growth factor-2 (FGF-2). By using atropine as nonselective mAChRs or pirenzepine as selective antagonist for M1receptor (M1R) we could show that mAChRs are involved in modulating the pFGFRs. Using PLA, M1R-FGFR1 heteroreceptor complexes were identified in the hippocampus and cerebral cortex. Conclusion The current findings, by showing functional mAChR-FGFR interactions, will contribute to advance the understanding of the mechanisms involved in the actions of cholinergic drugs on neuronal plasticity. General significant Data may help to develop novel therapeutic strategies not only for neurodegenerative diseases but also for depression-induced atrophy of hippocampal neurons.",
keywords = "FGFR1; Heteroreceptor complexes; M1receptor; Neural plasticity; Transactivation; Animals; Fibroblast Growth Factor 2; Hippocampus; Male; Neuronal Outgrowth; Neuronal Plasticity; Neurons; Oxotremorine; Rats; Rats, Fibroblast Growth Factor, Fibroblast Growth Factor; Receptors, G-Protein-Coupled; Receptors, Muscarinic M1; Receptors, Muscarinic; Signal Transduction; Biophysics; Biochemistry; Molecular Biology, Sprague-Dawley; Rats, Type 1; Receptor, Wistar; Receptor",
author = "Giuseppa Mudo' and Natale Belluardo and {Di Liberto}, Valentina and Borroto-Escuela, {Dasiel O.} and Fuxe and Monica Frinchi",
year = "2017",
language = "English",
volume = "1861",
pages = "235--245",
journal = "Biochimica et Biophysica Acta - General Subjects",
issn = "0006-3002",
publisher = "Elsevier",

}

TY - JOUR

T1 - Existence of muscarinic acetylcholine receptor (mAChR) and fibroblast growth factor receptor (FGFR) heteroreceptor complexes and their enhancement of neurite outgrowth in neural hippocampal cultures

AU - Mudo', Giuseppa

AU - Belluardo, Natale

AU - Di Liberto, Valentina

AU - Borroto-Escuela, Dasiel O.

AU - Fuxe, null

AU - Frinchi, Monica

PY - 2017

Y1 - 2017

N2 - Background Recently, it was demonstrated that G-protein-coupled receptors (GPCRs) can transactivate tyrosine kinase receptors in absence of their ligands. In this work, driven by the observation that mAChRs and fibroblast growth factor receptors (FGFRs) share signalling pathways and regulation of brain functions, it was decided to explore whether mAChRs activation may transactivate FGFRs and, if so, to characterize the related trophic effects in cultured hippocampal neurons. Methods Oxotremorine-M transactivation of FGFRs and related trophic effects were tested in primary hippocampal neurons. Western blotting and in situ proximity ligation assay (PLA) were used to detect FGFR phosphorylation (pFGFR) levels and M1R-FGFR1 heteroreceptor complexes, respectively. Results Oxotremorine-M, a non-selective mAChRs agonist, was able to transactivate FGFR and this transactivation was blocked by Src inhibitors. Oxotremorine-M treatment produced a significant increase in the primary neurite outgrowth that was blocked by pre-treatment with the pFGFR inhibitor SU5402 and Src inhibitors. This trophic effect was almost similar to that induced by fibroblast growth factor-2 (FGF-2). By using atropine as nonselective mAChRs or pirenzepine as selective antagonist for M1receptor (M1R) we could show that mAChRs are involved in modulating the pFGFRs. Using PLA, M1R-FGFR1 heteroreceptor complexes were identified in the hippocampus and cerebral cortex. Conclusion The current findings, by showing functional mAChR-FGFR interactions, will contribute to advance the understanding of the mechanisms involved in the actions of cholinergic drugs on neuronal plasticity. General significant Data may help to develop novel therapeutic strategies not only for neurodegenerative diseases but also for depression-induced atrophy of hippocampal neurons.

AB - Background Recently, it was demonstrated that G-protein-coupled receptors (GPCRs) can transactivate tyrosine kinase receptors in absence of their ligands. In this work, driven by the observation that mAChRs and fibroblast growth factor receptors (FGFRs) share signalling pathways and regulation of brain functions, it was decided to explore whether mAChRs activation may transactivate FGFRs and, if so, to characterize the related trophic effects in cultured hippocampal neurons. Methods Oxotremorine-M transactivation of FGFRs and related trophic effects were tested in primary hippocampal neurons. Western blotting and in situ proximity ligation assay (PLA) were used to detect FGFR phosphorylation (pFGFR) levels and M1R-FGFR1 heteroreceptor complexes, respectively. Results Oxotremorine-M, a non-selective mAChRs agonist, was able to transactivate FGFR and this transactivation was blocked by Src inhibitors. Oxotremorine-M treatment produced a significant increase in the primary neurite outgrowth that was blocked by pre-treatment with the pFGFR inhibitor SU5402 and Src inhibitors. This trophic effect was almost similar to that induced by fibroblast growth factor-2 (FGF-2). By using atropine as nonselective mAChRs or pirenzepine as selective antagonist for M1receptor (M1R) we could show that mAChRs are involved in modulating the pFGFRs. Using PLA, M1R-FGFR1 heteroreceptor complexes were identified in the hippocampus and cerebral cortex. Conclusion The current findings, by showing functional mAChR-FGFR interactions, will contribute to advance the understanding of the mechanisms involved in the actions of cholinergic drugs on neuronal plasticity. General significant Data may help to develop novel therapeutic strategies not only for neurodegenerative diseases but also for depression-induced atrophy of hippocampal neurons.

KW - FGFR1; Heteroreceptor complexes; M1receptor; Neural plasticity; Transactivation; Animals; Fibroblast Growth Factor 2; Hippocampus; Male; Neuronal Outgrowth; Neuronal Plasticity; Neurons; Oxotremorine; Rats; Rats

KW - Fibroblast Growth Factor

KW - Fibroblast Growth Factor; Receptors

KW - G-Protein-Coupled; Receptors

KW - Muscarinic M1; Receptors

KW - Muscarinic; Signal Transduction; Biophysics; Biochemistry; Molecular Biology

KW - Sprague-Dawley; Rats

KW - Type 1; Receptor

KW - Wistar; Receptor

UR - http://hdl.handle.net/10447/247663

UR - http://www.elsevier.com/locate/bbagen

M3 - Article

VL - 1861

SP - 235

EP - 245

JO - Biochimica et Biophysica Acta - General Subjects

JF - Biochimica et Biophysica Acta - General Subjects

SN - 0006-3002

ER -