Mammalian glial cells in culture synthesize acetylcholine

Wessler, Ignaz; Reinheimer, Torsten; Klapproth, Holger; Schneider, Franz-Josef; Racké, Kurt; Hammer, Rudolf

doi:10.1007/pl00005107

Cited by 46 publications

(31 citation statements)

References 9 publications

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“…Previous studies from our laboratory and other laboratories have shown that acetylcholine and M3 receptors are expressed in a wide variety of normal endothelial and epithelial cell types (5)(6)(7)(8)(9)(10)(11)(12)(13). This suggests that cancers derived from these diverse cell types will similarly coexpress acetylcholine and M3 receptors.…”

Section: Resultsmentioning

confidence: 75%

“…Recently, it has been established that acetylcholine is also widely synthesized by a variety of nonneuronal cell types, including keratinocytes (5), airway epithelial cells (6,7), glia (8), vascular endothelium (9, 10), placental trophoblasts (11), and ovarian follicular cells (12) among others (13). Expression of acetylcholine has been unambiguously shown in these cells and tissues as shown by the presence of choline acetyltransferase, the enzyme that synthesizes acetylcholine, and by demonstration of acetylcholine synthesis in these cells as measured by high-performance liquid chromatography (HPLC).…”

Section: Introductionmentioning

confidence: 99%

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M3 Muscarinic Receptor Antagonists Inhibit Small Cell Lung Carcinoma Growth and Mitogen-Activated Protein Kinase Phosphorylation Induced by Acetylcholine Secretion

et al. 2007

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The importance of acetylcholine as a neurotransmitter in the nervous system is well established, but little is yet known about its recently described role as an autocrine and paracrine hormone in a wide variety of nonneuronal cells. Consistent with the expression of acetylcholine in normal lung, small cell lung carcinoma (SCLC) synthesize and secrete acetylcholine, which acts as an autocrine growth factor through both nicotinic and muscarinic cholinergic mechanisms. The purpose of this study was to determine if interruption of autocrine muscarinic cholinergic signaling has potential to inhibit SCLC growth. Muscarinic receptor (mAChR) agonists caused concentration-dependent increases in intracellular calcium and mitogen-activated protein kinase (MAPK) and Akt phosphorylation in SCLC cell lines. The inhibitory potency of mAChR subtype-selective antagonists and small interfering RNAs (siRNAs) on acetylcholine-increased intracellular calcium and MAPK and Akt phosphorylation was consistent with mediation by M3 mAChR (M3R). Consistent with autocrine acetylcholine secretion stimulating MAPK and Akt phosphorylation, M3R antagonists and M3R siRNAs alone also caused a decrease in basal levels of MAPK and Akt phosphorylation in SCLC cell lines. Treatment of SCLC cells with M3R antagonists inhibited cell growth both in vitro and in vivo and also decreased MAPK phosphorylation in tumors in nude mice in vivo. Immunohistochemical staining of SCLC and additional cancer types showed frequent coexpression of acetylcholine and M3R. These findings suggest that M3R antagonists may be useful adjuvants for treatment of SCLC and, potentially, other cancers. [Cancer Res 2007;67(8):3936-44]

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Section: Resultsmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

M3 Muscarinic Receptor Antagonists Inhibit Small Cell Lung Carcinoma Growth and Mitogen-Activated Protein Kinase Phosphorylation Induced by Acetylcholine Secretion

et al. 2007

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“…Astrocytes cultured from neonatal mouse brain, contain significant levels of ACh (about 80 pmol/10 6 cells) as well as activity of ChAT, suggesting the endogenous production of ACh in these cells (Wessler et al, 1997). In addition, a recent report indicates that synaptically released ACh in hippocampal slices can activate muscarinic receptors on astrocytes (Araque et al, 2002).…”

Section: Possible Sources Of Ach For Nachr Activation In Nonexcitablementioning

confidence: 99%

Nicotinic receptor signaling in nonexcitable cells

2002

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ABSTRACT:The finding that neuronal nicotinic acetylcholine receptors (nAChRs) are present in nonneuronal cells both within and outside the nervous system raises some interesting issues. The mechanisms underlying receptor signaling and its downstream consequences in these cells remain to be elucidated. Factors controlling the release of acetylcholine and the extent of its diffusion are likely to be different for these cells than for traditional neuronal synapses. Recent advances on the physiologic functions of some of these cell types have provided a better insight into possible functional roles for nAChRs in nonexcitable cells. The presence of nAChRs on these cells also implies a broader scope for the actions of nicotine that needs to be considered from a clinical viewpoint. Revealing the potential physiologic roles for nAChRs on nonexcitable cells is likely to provide a more complete understanding of cholinergic signaling.

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“…The recent discovery that lung cancers synthesize and secrete acetylcholine (ACh) that acts as an autoparacrine growth factor provides potential new targets to inhibit lung cancer growth. 3,4 It is well established that ACh is an important neurotransmitter in the central and peripheral nervous systems and acts via activation of ACh receptors (AChRs).Recently, it has been found that ACh is also widely synthesized by a variety of non-neuronal cell types including airway epithelial cells, 5,6 keratinocytes, 7 small and large intestine, gall bladder, 8 glial, 9 vascular endothelial, 10 immune cells and most common cancer cells such as NSCLC, SCLC, colon, glial and ovarian carcinomas. [11][12][13][14][15][16] Although the primary function has not yet been completely elucidated, the expression of ACh in many different cell types suggests that its roles will be fundamental and will present novel therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Blocking M2 muscarinic receptor signaling inhibits tumor growth and reverses epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC)

Zhao

Zhang

et al. 2015

Cancer Biology & Therapy

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These authors contributed equally to this work.Keywords: autoparacrine, AKT, epithelial-mesenchymal transition, MAPK ERK, M2 muscarinic receptor, non-neuronal acetylcholine, non-small cell lung cancerAbbreviations: NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; ACh, acetylcholine; AChR, acetylcholine receptor; mAChR, muscarinic receptor; nAChR, nicotinic receptor; M2R, M2 mAChR; EMT, epithelial-mesenchymal transition; ChAT, choline acetyltransferase; MAPK, mitogen-activated protein kinase; shRNA, short hairpin RNA.Lung cancers express non-neuronal, cholinergic autoparacrine loop, which facilitates tumor growth. Interruption of M3 muscarinic cholinergic signaling has been reported to inhibit small cell lung cancer (SCLC) growth. The purpose of this study is to investigate if blocking autoparacrine muscarinic cholinergic signaling could inhibit non-small cell lung cancer (NSCLC) growth and possible underlying mechanisms. Our results showed that PC9 and A549 cells expressed all 5 subtypes of muscarinic receptor (mAChR) and blocking M2 mAChR (M2R) signaling using selective antagonist methoctramine or short hairpin RNA (shRNA) inhibited tumor cell proliferation in vitro and in vivo. Consistent with AChR agonists stimulating p44/42 MAPK (Erk1/2) and Akt phosphorylation, blocking M2R signaling decreased MAPK and Akt phosphorylation, indicating that non-neuronal ACh functions as an autoparacrine growth factor signaling in part through activation of M2R and downstream MAPK and Akt pathways. Importantly, further studies revealed that blocking M2R signaling also reversed epithelial-mesenchymal transition (EMT) in vitro and in vivo, indicating that nonneuronal ACh promotes EMT partially through activation of M2R. These findings demonstrate that M2R plays a role in the growth and progression of NSCLC and suggest M2R antagonists may be an efficacious adjuvant therapy for NSCLC.

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Mammalian glial cells in culture synthesize acetylcholine

Cited by 46 publications

References 9 publications

M3 Muscarinic Receptor Antagonists Inhibit Small Cell Lung Carcinoma Growth and Mitogen-Activated Protein Kinase Phosphorylation Induced by Acetylcholine Secretion

M3 Muscarinic Receptor Antagonists Inhibit Small Cell Lung Carcinoma Growth and Mitogen-Activated Protein Kinase Phosphorylation Induced by Acetylcholine Secretion

Nicotinic receptor signaling in nonexcitable cells

Blocking M2 muscarinic receptor signaling inhibits tumor growth and reverses epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC)

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