Potential clozapine target sites on peripheral hematopoietic cells and stromal cells of the bone marrow

Pereira, Alda; McLaren, Andrew; Bell, William R.; Copolov, David L.; Dean, Brian

doi:10.1038/sj.tpj.6500179

Cited by 29 publications

(18 citation statements)

References 56 publications

(68 reference statements)

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“…3). The expression of MR is known in hematopoietic cells and stromal cells of the bone marrow (Pereira et al 2003) but not for bone itself. The role of MR is also well established during bone perfusion.…”

Section: Discussionmentioning

confidence: 99%

Expression of non-neuronal cholinergic system in osteoblast-like cells and its involvement in osteogenesis

et al. 2009

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Acetylcholine (ACh) is detected in a variety of non-neuronal cells where it acts as a para/autocrine signaling molecule controlling basic cell functions such as proliferation, differentation, and maintenance of cell-cell contacts. ACh-synthesizing enzymes include choline acetyltransferase and carnitine acetyltransferase (CarAT). ACh is released through vesicular exocytosis or directly from the cytoplasm via organic cation transporters (OCT). Extracellular ACh binds to nicotinic (nAChR) and muscarinic receptors (MR). Degradation of ACh is performed by acetylcholinesterase and butyrylcholinesterase (BChE). Here, we have determined whether these molecules are expressed in osteoblast-like cells, by means of reverse transcription polymerase chain reaction and immunohistochemistry, focusing on nAChR subunits alpha3 and alpha5. RNA for CarAT, OCT-1, M2R, M5R, nAChR subunits alpha3, alpha5, alpha9, alpha10, beta2, beta3, and BChE were detected in human (SAOS-2) and murine (MC3T3-E1) osteoblast-like cells. Other cholinergic components were only expressed species-specifically, e.g., M3R and nAChR subunit alpha7. Immunhistochemistry localized the nAChR subunits alpha3 and alpha5 in osteoblasts in vitro and in vivo where they were up-regulated after application of bone morphogenetic protein-2 (BMP-2) during fracture healing in a rat model. Thus, the cholinergic system of osteoblast-like cells might be regulated by BMP-2 during bone remodeling. Osteoblast-like cells express all necessary enzymes, transporters, and receptors for ACh synthesis and recycling.

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Section: Discussionmentioning

confidence: 99%

Expression of non-neuronal cholinergic system in osteoblast-like cells and its involvement in osteogenesis

et al. 2009

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“…In addition, fibroblasts were plated onto six-well culture plates for the proliferation studies and cellular stimulation. Only early passage cells (1-3) were used for each experiment to avoid problems that may occur in the higher number of passage cells and the expression of MRs (Bany et al, 1999;Nicke et al, 1999;Pereira et al, 2003).…”

Section: Methodsmentioning

confidence: 99%

Smoke, Choline Acetyltransferase, Muscarinic Receptors, and Fibroblast Proliferation in Chronic Obstructive Pulmonary Disease

Profita¹,

Bonanno²,

Siena³

et al. 2009

J Pharmacol Exp Ther

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Acetylcholine (ACh), synthesized by choline acetyltransferase (ChAT), and muscarinic M 1 , M 2 , and M 3 receptors (MRs) are involved in fibroblast proliferation. We evaluated ChAT, MRs, and extracellular signal-regulated kinase (ERK) 1/2 and nuclear factor (NF) B activation in lung fibroblasts from patients with chronic obstructive pulmonary disease (COPD), control smokers, and controls. Human fetal lung fibroblasts (HFL-1) stimulated with interleukin (IL)-1␤, tumor necrosis factor (TNF)-␣, and cigarette smoke extracts (CSEs) were evaluated for ChAT and MR expression. We tested the effects of ACh on fibroblast proliferation and its ability to bind fibroblasts from patients with COPD, control smokers, controls, and HFL-1 stimulated with IL-1␤, TNF-␣, and CSE. ChAT, M 1 , and M 3 expression and ERK1/2 and NFB activation were increased, whereas M 2 was reduced, in COPD and smoker subjects compared with controls. IL-1␤ increased the ChAT and M 3 , TNF-␣ down-regulated M 2 , and CSE increased ChAT and M 3 expression while downregulating the expression of M 2 in HFL-1 cells. ACh stimulation increased fibroblast proliferation in patients with COPD, control smokers, and controls, with higher effect in control smokers and patients with COPD and increased HFL-1 proliferation only in CSE-treated cells. The binding of ACh was higher in patients with COPD and in control smokers than in controls and in CSE-treated than in IL-1␤-and TNF-␣-stimulated HFL-1 cells. Tiotropium (Spiriva; [1␣,2␤,4␤,5␣,7␤-7-hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatrcyclo[3.3. [(E)-3-(4-methylphenylsulfonyl)-2-propenetrile, C 10 H 9 NO 2 C], down-regulated the ACh-induced fibroblast proliferation, promoting the MRs and ERK1/2 and NFB pathways involvement in this phenomenon. These results suggest that cigarette smoke might alter the expression of ChAT and MRs, promoting airway remodeling in COPD and that anticholinergic drugs, including tiotropium, might prevent these events.An overpresence of fibroblasts has been observed in chronic airway diseases and several factors, released by both parenchymal and inflammatory cells, can contribute to this event promoting fibroblast proliferation (Jeffery, 1998 ABBREVIATIONS: M 1 , muscarinic M 1 receptor; M 2 , muscarinic M 2 receptor; M 3 , muscarinic M 3 receptor; MR, muscarinic M 1 , M 2 , and M 3 receptor; MAPK, mitogen-activated protein kinase; ACh, acetylcholine; ChAT, choline acetyltransferase; COPD, chronic obstructive pulmonary disease; IL, interleukin; TNF, tumor necrosis factor; CS, cigarette smoke; ERK, extracellular signal-regulated kinase; NF, nuclear factor; CSE, cigarette smoke extract; C, asymptomatic nonsmoking subject(s) with normal lung function; FBS, fetal bovine serum; PAGE, polyacrylamide gel electrophoresis; FITC, fluorescein isothiocyanate; ELISA, enzyme-linked immunosorbent assay; pNFB, phosphorylated NFB; tNFB, total NFB; tiotropium, Spiriva, [1␣,2␤,4␤,5␣,7␤-7-hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatrcyclo[3.3. O; 4-DAMP, 4-diphenylacetoxy-N...

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“…1a) are considered responsible for many drug side-effects, such as those of the antipsychotic clozapine molecule [41,42]. The oxidation behavior of clozapine was elucidated by Blankert et al using EC-MS [43].…”

Section: Iminium Reactive Metabolitesmentioning

confidence: 99%

Electrochemistry-mass spectrometry to study reactive drug metabolites and CYP450 simulations

Bussy

Boisseau

Thobie‐Gautier

et al. 2015

TrAC Trends in Analytical Chemistry

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Potential clozapine target sites on peripheral hematopoietic cells and stromal cells of the bone marrow

Cited by 29 publications

References 56 publications

Expression of non-neuronal cholinergic system in osteoblast-like cells and its involvement in osteogenesis

Expression of non-neuronal cholinergic system in osteoblast-like cells and its involvement in osteogenesis

Smoke, Choline Acetyltransferase, Muscarinic Receptors, and Fibroblast Proliferation in Chronic Obstructive Pulmonary Disease

Electrochemistry-mass spectrometry to study reactive drug metabolites and CYP450 simulations

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