Up-regulation of the levels of expression and function of a constitutively active mutant of the hamster alpha1B-adrenoceptor by ligands that act as inverse agonists.

Details

Serval ID
serval:BIB_7122DCCA1A7E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Up-regulation of the levels of expression and function of a constitutively active mutant of the hamster alpha1B-adrenoceptor by ligands that act as inverse agonists.
Journal
Biochemical Journal
Author(s)
Lee T.W., Cotecchia S., Milligan G.
ISSN
0264-6021 (Print)
ISSN-L
0264-6021
Publication state
Published
Issued date
1997
Volume
325
Number
3
Pages
733-739
Language
english
Abstract
The alpha1-adrenergic agonist phenylephrine stimulated phospholipase D (PLD) activity in Rat 1 fibroblasts transfected to express either the wild-type hamster alpha1B-adrenoceptor or a constitutively active mutant (CAM) form of this receptor. The EC50 for agonist stimulation of PLD activity was substantially lower at the CAM receptor than at the wild-type receptor as previously noted for phenylephrine stimulation of phosphoinositidase C activity. Sustained treatment of cells expressing the CAM alpha1B-adrenoceptor with phentolamine resulted in a marked up-regulation in levels of this receptor with half-maximal effects produced within 24 h and with an EC50 of approx. 40 nM. Such an up-regulation could be produced with a range of other ligands generally viewed as alpha1-adrenoceptor antagonists but equivalent treatment of cells expressing the wild-type alpha1B-adrenoceptor was unable to mimic these effects. After sustained treatment of the CAM alpha1B-adrenoceptor expressing cells with phentolamine, basal PLD activity was increased and phenylephrine was now able to stimulate PLD activity to greater levels than in vehicle-treated CAM alpha1B-adrenoceptor-expressing cells. The EC50 for phenylephrine stimulation of PLD activity was not altered, however, by phentolamine pretreatment and the associated up-regulation of the receptor. After phentolamine-induced up-regulation of basal PLD activity, a range of alpha1-antagonists were shown to possess the characteristics of inverse agonists of the CAM alpha1B-adrenoceptor as they were able to substantially decrease the elevated basal PLD activity.
Keywords
Adrenergic alpha-1 Receptor Agonists, Adrenergic alpha-Agonists/metabolism, Adrenergic alpha-Agonists/pharmacology, Animals, Cricetinae, DNA, Complementary, Ligands, Mutagenesis, Phospholipase D/metabolism, Prazosin/metabolism, Prazosin/pharmacology, Rats, Receptors, Adrenergic, alpha-1/genetics, Receptors, Adrenergic, alpha-1/metabolism, Up-Regulation
Pubmed
Web of science
Create date
24/01/2008 11:05
Last modification date
20/08/2019 14:29
Usage data