期刊
PHARMACOLOGICAL RESEARCH
卷 64, 期 4, 页码 420-425出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2011.06.009
关键词
UROtsa cell line; Muscarinic receptors; Acetylcholine; Cell proliferation
资金
- University of Brescia
- European Community [HEALTH-F2-2008-223234]
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 mu M) concentration-dependently raised IP3 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 mu M CCh: 0.84 +/- 0.12 pmol/ml). CCh (1-100 mu M) 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. (C) 2011 Elsevier Ltd. All rights reserved.
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