The interaction of U-73122 with the histamine H 1 receptor: implications for the use of U-73122 in defining H 1 receptor-coupled signalling pathways

Hughes, Simon; Gibson, W. J.; Young, J. M.

doi:10.1007/s002100000326

Cited by 25 publications

(3 citation statements)

References 6 publications

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“…U73122 is a steroid derivative that might directly activate CatSper channels. Moreover, U73122 is not very specific; in somatic cells, the drug inhibits Ca 2+ pumps, releases Ca 2+ from intracellular stores, activates and inhibits ion channels, and binds to GPCRs (Mogami et al , 1997; Hughes et al , 2000; Macmillan and McCarron, 2010). Thus, U73122—like MDL12330A and SQ22536—is ill suited to investigate Ca 2+ signalling in sperm.…”

Section: Resultsmentioning

confidence: 99%

The CatSper channel: a polymodal chemosensor in human sperm

et al. 2012

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The sperm-specific CatSper channel controls the intracellular Ca(2+) concentration ([Ca(2+)](i)) and, thereby, the swimming behaviour of sperm. In humans, CatSper is directly activated by progesterone and prostaglandins-female factors that stimulate Ca(2+) influx. Other factors including neurotransmitters, chemokines, and odorants also affect sperm function by changing [Ca(2+)](i). Several ligands, notably odorants, have been proposed to control Ca(2+) entry and motility via G protein-coupled receptors (GPCRs) and cAMP-signalling pathways. Here, we show that odorants directly activate CatSper without involving GPCRs and cAMP. Moreover, membrane-permeable analogues of cyclic nucleotides that have been frequently used to study cAMP-mediated Ca(2+) signalling also activate CatSper directly via an extracellular site. Thus, CatSper or associated protein(s) harbour promiscuous binding sites that can host various ligands. These results contest current concepts of Ca(2+) signalling by GPCR and cAMP in mammalian sperm: ligands thought to activate metabotropic pathways, in fact, act via a common ionotropic mechanism. We propose that the CatSper channel complex serves as a polymodal sensor for multiple chemical cues that assist sperm during their voyage across the female genital tract.

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Section: Resultsmentioning

confidence: 99%

The CatSper channel: a polymodal chemosensor in human sperm

et al. 2012

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“…U-73122 was frequently used to define the role of PLC mediated elevation of intracellular calcium concentration, indirectly used as a tool to investigate the PLCs’ signal transduction. However, lack of selectivity of PLC inhibition by U-73122 was described, as it acts (Cenni and Picard 1999 ) upon a number of unrelated proteins (Feisst et al 2005 ; Hughes et al 2000 ; Walker et al 1998 ; Berven and Barritt 1995 ; Pulcinelli et al 1998 ). U-73122 PLC inhibiting activity is due to prevention of the turnover of PI, thus avoiding the formation of the second messengers IP3 and DAG (Vickers and Fisher 2004 ; Thomas et al 2005 ).…”

Section: Discussionmentioning

confidence: 99%

U-73122 reduces the cell growth in cultured MG-63 ostesarcoma cell line involving Phosphoinositide-specific Phospholipases C

et al. 2016

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The definition of the number and nature of the signal transduction pathways involved in the pathogenesis and the identification of the molecules promoting metastasis spread might improve the knowledge of the natural history of osteosarcoma, also allowing refine the prognosis and opening the way to novel therapeutic strategies. Phosphatydil inositol (4,5) bisphosphate (PIP2), belonging to the Phosphoinositide (PI) signal transduction pathway, was related to the regulation of ezrin, an ezrin–radixin–moesin protein involved in metastatic osteosarcoma spread. The levels of PIP2 are regulated by means of the PI-specific Phospholipase C (PLC) enzymes. Recent literature data suggested that in osteosarcoma the panel of expression of PLC isoforms varies in a complex and unclear manner and is related to ezrin, probably networking with Ras GTPases, such as RhoA and Rac1. We analyzed the expression and the subcellular localization of PLC enzymes in cultured human osteosarcoma MG-63 cells, commonly used as an experimental model for human osteoblasts, using U-73122 PLC inhibitor, U-73343 inactive analogue, and by silencing ezrin. The treatment with U-73122 significantly reduces the number of MG-63 viable cells and contemporarily modifies the expression and the subcellular localization of selected PLC isoforms. U-73122 reduces the cell growth in cultured MG-63 ostesarcoma cell line involving PI-specific Phospholipases C.

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“…PLC has been suggested to be activated non-selectively by the small molecule m3M3FBS 218, although this mechanism of action has been questioned 235. The aminosteroid U73122 has been described as an inhibitor of phosphoinositide-specific PLC 257, although its selectivity among the isoforms is untested and it has been reported to occupy the H1 histamine receptor 230.…”

Section: Glycerophospholipid Turnovermentioning

confidence: 99%

The Concise Guide to PHARMACOLOGY 2013/14: Enzymes

Alexander

Benson

Faccenda

et al. 2013

British J Pharmacology

438

127

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The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full.Enzymes are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets.It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.

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The interaction of U-73122 with the histamine H 1 receptor: implications for the use of U-73122 in defining H 1 receptor-coupled signalling pathways

Cited by 25 publications

References 6 publications

The CatSper channel: a polymodal chemosensor in human sperm

The CatSper channel: a polymodal chemosensor in human sperm

U-73122 reduces the cell growth in cultured MG-63 ostesarcoma cell line involving Phosphoinositide-specific Phospholipases C

The Concise Guide to PHARMACOLOGY 2013/14: Enzymes

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