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Titolo:
Dynamics of P2X(7) receptor pore dilation: Pharmacological and functional consequences
Autore:
Chessell, IP; Grahames, CBA; Michel, AD; Humphrey, PPA;
Indirizzi:
Glaxo Wellcome Inc, Med Res Ctr, Stevenage SG1 2NY, Herts, England Glaxo Wellcome Inc Stevenage Herts England SG1 2NY G1 2NY, Herts, England Pfizer Ltd, Sandwich, Kent, England Pfizer Ltd Sandwich Kent EnglandPfizer Ltd, Sandwich, Kent, England Glaxo Inst Appl Pharmacol, Cambridge, England Glaxo Inst Appl Pharmacol Cambridge England armacol, Cambridge, England
Titolo Testata:
DRUG DEVELOPMENT RESEARCH
fascicolo: 2-3, volume: 53, anno: 2001,
pagine: 60 - 65
SICI:
0272-4391(200106/07)53:2-3<60:DOPRPD>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACETYLCHOLINE-RECEPTOR; NUCLEOTIDE RECEPTOR; IL-1-BETA RELEASE; ATP; ANTIBODIES; INDUCTION;
Keywords:
P2X(7); purinoceptor; interleukin; pore dilation;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
20
Recensione:
Indirizzi per estratti:
Indirizzo: Chessell, IP Glaxo Wellcome Inc, Med Res Ctr, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England Glaxo Wellcome Inc Gunnels Wood Rd Stevenage Herts England SG1 2NY
Citazione:
I.P. Chessell et al., "Dynamics of P2X(7) receptor pore dilation: Pharmacological and functional consequences", DRUG DEV R, 53(2-3), 2001, pp. 60-65

Abstract

The biophysical and functional properties of the human P2X(7) receptor, expressed recombinantly in HEK-293 cells or natively in THP-1 pro-monocytic cells, were investigated in the context of pore dilation and externalisationof mature interleukin 1 beta (IL1 beta). In HEK-293 cells, the agonist 2'-and 3'-O-(4-benzoylbenzoyl)-ATP (BzATP) caused concentration-dependent inward currents (EC50 59 muM) and with prolonged application this agonist caused a gradual increase in inward current culminating in a plateau. This increase in current was associated with pore dilation, determined by intracellular accumulation of YO-PRO-1. BzATP displayed increased potency at the pore-dilated form of the P2X(7) receptor (EC50 17 muM), and positive correlations between apparent receptor density and speed of pore dilation were observed. A monoclonal antibody selectively blocked current mediated by the naivereceptor, while currents through pore-dilated receptors were not significantly affected, which together suggest a conformational change at the level of the receptor during the dilation event. The release of mature IL1 beta from THP-1 cells was independent of P2X(7)-mediated cell lysis, as determined by study of lactate dehydrogenase release. Moreover, using conditions designed to minimise pore dilation (using buffers containing 2 mM Ca2+ and 1 mm Mg2+), BzATP caused significant release of IL1 beta, but without concomitant YO-PRO-1 accumulation, indicating pore dilation is not required for IL1beta release. In addition, short (4-min) incubation of THP-1 cells with BzATP (terminated by enzymatic degradation of BzATP using apyrase) resulted in significant quantities of IL1 beta release some 60 min later, suggesting commitment of cells to release IL1 beta can be triggered with only brief receptor ligation. These findings suggest that receptor expression and ligation time are critical factors for selecting multiple functional states of P2X(7). (C) 2001 Wiley-Liss, Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/11/20 alle ore 07:33:02