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Titolo:
Specific inhibition of the rat ligand-gated ion channel P2X3 function via methoxyethoxy-modified phosphorothioated antisense oligonucleotides
Autore:
Dorn, G; Abdelal, S; Natt, FJC; Weiler, J; Hall, J; Meigel, I; Mosbacher, J; Wishart, W;
Indirizzi:
Novartis Pharma AG, Funct Gen, CH-4002 Basel, Switzerland Novartis Pharma AG Basel Switzerland CH-4002 CH-4002 Basel, Switzerland Novartis Pharma AG, Nervous Syst Res, CH-4002 Basel, Switzerland Novartis Pharma AG Basel Switzerland CH-4002 CH-4002 Basel, Switzerland
Titolo Testata:
ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT
fascicolo: 3, volume: 11, anno: 2001,
pagine: 165 - 174
SICI:
1087-2906(200106)11:3<165:SIOTRL>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
P2X(3) RECEPTOR SUBUNITS; SENSORY NEURONS; IMMUNOCYTOCHEMICAL LOCALIZATION; URINARY-BLADDER; ATP; PAIN; EXPRESSION; PURINOCEPTOR; MICE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
31
Recensione:
Indirizzi per estratti:
Indirizzo: Wishart, W Novartis Pharma AG, Funct Gen, WSJ-360 605, CH-4002 Basel, Switzerland Novartis Pharma AG WSJ-360 605 Basel Switzerland CH-4002 rland
Citazione:
G. Dorn et al., "Specific inhibition of the rat ligand-gated ion channel P2X3 function via methoxyethoxy-modified phosphorothioated antisense oligonucleotides", ANTISENSE N, 11(3), 2001, pp. 165-174

Abstract

P2X3 is one receptor of a family of seven ligand-gated ion channels responding to purines, Increasing evidence indicates its involvement in neuronal signaling and in pain. However, there is currently no selective inhibitor known for this subtype, In order to obtain such a specific inhibitor, a variety of antisense oligonucleotides (ASO) against rat P2X3 was tested, and dose-dependent, sequence-specific downregulation of the rat P2X3 receptor (expressed in a Chinese hamster ovary cell line [CHO-K1]) on the mRNA, protein, and functional levels was observed. Using real-time quantitative PCR, a dose-dependent downregulation of P2X3 mRNA by ASO, as compared with untreated and mismatch controls, was demonstrated. Subsequently, downregulation by the two most potent ASO was confirmed at the protein level by Western blot. Sequence specificity was shown by titration of mismatches to the original selected oligonueleotide, and this correlated with progressive loss of P2X3inhibition. The functional response of the P2X3 receptor was examined using whole-cell voltage clamping, Upon application of 10 muM of a nonspecific agonist, alpha,beta -methylene-ATP (alpha beta meATP), pretreatment with increasing amounts of the most active ASO 5037 correlated with a decrease in depolarization. The ability to specifically downregulate the P2X3 receptor by ASO treatment will allow investigation of the biologic role of this receptor in neuronal tissues and eventually in in vivo models of chronic pain.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 10/04/20 alle ore 02:41:45