Muscarinic receptors stimulate cell proliferation in the human urothelium-derived cell line UROtsa

Nicola Arrighi, Serena Bodei, Alessandra Lucente, Martin C. Michel, Danilo Zani, Claudio Simeone, Sergio Cosciani Cunico, Pierfranco Spano, Sandra Sigala

Research output: Contribution to journalArticle

Abstract

The widespread non-neuronal synthesis of acetylcholine (ACh) has changed the paradigm of ACh acting solely as a neurotransmitter. Indeed, the presence of ACh in many types of proliferating cells suggests a role for this neurotransmitter in the control of cell division. The parasympathetic system is a major pathway regulating micturition, but ACh-mediated control plays a more complex role than previously described, acting not only in the detrusor muscle, but also influencing detrusor function through the activity of urothelial muscarinic receptors. Here we investigated the role of muscarinic receptors in mediating cell proliferation in the human UROtsa cell line, which is a widely used experimental model to study urothelium physiology and pathophysiology. Our results demonstrate that UROtsa cells express the machinery for ACh synthesis and that muscarinic receptors, with the rank order of M 3 > M 2 > M 5 > M 1 = M 4, are present and functionally linked to their known second messengers. Indeed, the cholinergic receptor agonist carbachol (CCh) (1-100 μM) concentration- dependently raised IP 3 levels, reaching 66 ± 5% over basal. The forskolin-mediated adenylyl cyclase activation was reduced by CCh exposure (forskolin: 1.4 ± 0.14 pmol/ml; forskolin + 100 μM CCh: 0.84 ± 0.12 pmol/ml). CCh (1-100 μM) concentration-dependently increased UROtsa cell proliferation and this effect was inhibited by the non-selective antagonist atropine and the M 3-selective antagonists darifenacin and J104129. Finally, CCh-induced cell proliferation was blocked by selective PI-3 kinase and ERK activation inhibitors, strongly suggesting that these intracellular pathways mediate, at least in part, the muscarinic receptor-mediated cell proliferation.

Original languageEnglish
Pages (from-to)420-425
Number of pages6
JournalPharmacological Research
Volume64
Issue number4
DOIs
Publication statusPublished - Oct 2011

Keywords

  • Acetylcholine
  • Cell proliferation
  • Muscarinic receptors
  • UROtsa cell line

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    Arrighi, N., Bodei, S., Lucente, A., Michel, M. C., Zani, D., Simeone, C., Cunico, S. C., Spano, P., & Sigala, S. (2011). Muscarinic receptors stimulate cell proliferation in the human urothelium-derived cell line UROtsa. Pharmacological Research, 64(4), 420-425. https://doi.org/10.1016/j.phrs.2011.06.009