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Titolo:
REGULATION OF MUSCARINIC M(2) RECEPTORS
Autore:
BARNES PJ; HADDAD EB; ROUSELL J;
Indirizzi:
NATL HEART & LUNG INST,IMPERIAL COLL,SCH MED,DEPT THORAC MED,DOVEHOUSE ST LONDON SW3 ENGLAND
Titolo Testata:
Life sciences
fascicolo: 13-14, volume: 60, anno: 1997,
pagine: 1015 - 1021
SICI:
0024-3205(1997)60:13-14<1015:ROMMR>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
INDUCED DOWN-REGULATION; MESSENGER-RNA; HUMAN LUNG; PROTEIN; CARBACHOL; SUBTYPES; AIRWAYS; CELLS;
Keywords:
M(2) RECEPTORS; CYTOKINES; PROTEIN KINASE C; MAP KINASE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
29
Recensione:
Indirizzi per estratti:
Citazione:
P.J. Barnes et al., "REGULATION OF MUSCARINIC M(2) RECEPTORS", Life sciences, 60(13-14), 1997, pp. 1015-1021

Abstract

The molecular mechanisms involved in the regulation of muscarinic receptor gene expression are poorly understood. In an effort to gain a better understanding of the regulation of M(2) receptors, we have investigated homologous and heterologous regulation of M(2) muscarinic receptor protein and gene expression in human embryonic lung fibroblasts (HEL 299 cells). HEL 299 cells constitutively express m2 receptors, withno evidence of other muscarinic receptor subtypes. We have shown thatbeta(2)-receptors in these cells can be down-regulated by muscarinic and beta(2)-adrenergic receptor agonists. Unlike the down-regulation mediated by muscarinic and beta-adrenergic stimulation, activation of PKC with PDBu was mediated through changes in m2 muscarinic receptor mRNA through reduced gene transcription. Because of the inflammatory nature of asthma, we have focused on delineating the interactions betweencytokines and M(2) receptors in an attempt to define potential endogenous modulators of M(2) receptor expression. We have shown that the multi-functional cytokine, transforming growth factor beta 1 (TGF-beta 1), which is involved in several inflammatory conditions induces desensitization and down-regulation of M(2) muscarinic receptor protein and gene expression that was mediated through a reduction in the rate of m2 receptor gene transcription. Other cytokines of interest are tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) which are elevated in asthma. We have demonstrated that TNF-alpha and IL-1 beta synergise to induce down-regulation of M(2) muscarinic receptor protein and mRNA which was associated with functional desensitization of the receptor protein. The M(2) receptor mRNA down-regulation appeared to be mediated through a reduction in the rate of m2 receptor gene transcription which may be dependent on the transcription and translation of unknown protein factor(s). Moreover, a role of PKA and ceramide pathways in M(2) receptor regulation is suggested. Collectively, our work provides a mechanistic explanation of previous reports indicating altered function of M(2) receptors in asthma. Ours results also suggest that the expression of this receptor subtype may be under the control of a cytokine network at the airways.

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Documento generato il 25/11/20 alle ore 01:20:06