Inhibition of beta-adrenergic receptor kinase prevents rapid homologous
desensitization of beta 2-adrenergic receptors
M. Lohse, R. Lefkowitz, M. Caron, and J. Benovic. Proc Natl Acad Sci U S A, 86 (9):
3011-5(May 1989)Lohse, M J Lefkowitz, R J Caron, M G Benovic, J L Comparative Study
Research Support, Non-U.S. Gov't United states Proceedings of the
National Academy of Sciences of the United States of America Proc
Natl Acad Sci U S A. 1989 May;86(9):3011-5..
Abstract
Homologous (agonist-specific) desensitization of beta-adrenergic receptors
(beta ARs) is accompanied by and appears to require phosphorylation
of the receptors. We have recently described a novel protein kinase,
beta AR kinase, which phosphorylates beta ARs in vitro in an agonist-dependent
manner. This kinase is inhibited by two classes of compounds, polyanions
and synthetic peptides derived from the beta 2-adrenergic receptor
(beta 2AR). In this report we describe the effects of these inhibitors
on the process of homologous desensitization induced by the beta-adrenergic
agonist isoproterenol. Permeabilization of human epidermoid carcinoma
A431 cells with digitonin was used to permit access of the charged
inhibitors to the cytosol; this procedure did not interfere with
the pattern of isoproterenol-induced homologous desensitization of
beta 2AR-stimulated adenylyl cyclase. Inhibitors of beta AR kinase
markedly inhibited homologous desensitization of beta 2ARs in the
permeabilized cells. Inhibition of desensitization by heparin, the
most potent of the polyanion inhibitors of beta AR kinase, occurred
over the same concentration range (5-50 nM) as inhibition of purified
beta AR kinase assessed in a reconstituted system. Inhibition of
desensitization by heparin was accompanied by a marked reduction
of receptor phosphorylation in the permeabilized cells. Whereas inhibitors
of beta AR kinase inhibited homologous desensitization, inhibitors
of protein kinase C and of cyclic-nucleotide-dependent protein kinases
were ineffective. These data establish that phosphorylation of beta
ARs by beta AR kinase is an essential step in homologous desensitization
of the receptors. They further suggest a potential therapeutic value
of inhibitors of beta AR kinase in inhibiting agonist-induced desensitization.
Lohse, M J Lefkowitz, R J Caron, M G Benovic, J L Comparative Study
Research Support, Non-U.S. Gov't United states Proceedings of the
National Academy of Sciences of the United States of America Proc
Natl Acad Sci U S A. 1989 May;86(9):3011-5.
%0 Journal Article
%1 Lohse1989a
%A Lohse, M. J.
%A Lefkowitz, R. J.
%A Caron, M. G.
%A Benovic, J. L.
%D 1989
%J Proc Natl Acad Sci U S A
%K *Protein Animals Cell Cricetinae Cultured Digitonin Drug Heparin/pharmacology Humans Inhibitors Isoproterenol/pharmacology Kinase Kinetics Lung/analysis Membrane Permeability Phosphorylation Tolerance Tumor beta/drug effects/*metabolism Receptor Adrenergic
%N 9
%P 3011-5
%T Inhibition of beta-adrenergic receptor kinase prevents rapid homologous
desensitization of beta 2-adrenergic receptors
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2541428
%V 86
%X Homologous (agonist-specific) desensitization of beta-adrenergic receptors
(beta ARs) is accompanied by and appears to require phosphorylation
of the receptors. We have recently described a novel protein kinase,
beta AR kinase, which phosphorylates beta ARs in vitro in an agonist-dependent
manner. This kinase is inhibited by two classes of compounds, polyanions
and synthetic peptides derived from the beta 2-adrenergic receptor
(beta 2AR). In this report we describe the effects of these inhibitors
on the process of homologous desensitization induced by the beta-adrenergic
agonist isoproterenol. Permeabilization of human epidermoid carcinoma
A431 cells with digitonin was used to permit access of the charged
inhibitors to the cytosol; this procedure did not interfere with
the pattern of isoproterenol-induced homologous desensitization of
beta 2AR-stimulated adenylyl cyclase. Inhibitors of beta AR kinase
markedly inhibited homologous desensitization of beta 2ARs in the
permeabilized cells. Inhibition of desensitization by heparin, the
most potent of the polyanion inhibitors of beta AR kinase, occurred
over the same concentration range (5-50 nM) as inhibition of purified
beta AR kinase assessed in a reconstituted system. Inhibition of
desensitization by heparin was accompanied by a marked reduction
of receptor phosphorylation in the permeabilized cells. Whereas inhibitors
of beta AR kinase inhibited homologous desensitization, inhibitors
of protein kinase C and of cyclic-nucleotide-dependent protein kinases
were ineffective. These data establish that phosphorylation of beta
ARs by beta AR kinase is an essential step in homologous desensitization
of the receptors. They further suggest a potential therapeutic value
of inhibitors of beta AR kinase in inhibiting agonist-induced desensitization.
@article{Lohse1989a,
abstract = {Homologous (agonist-specific) desensitization of beta-adrenergic receptors
(beta ARs) is accompanied by and appears to require phosphorylation
of the receptors. We have recently described a novel protein kinase,
beta AR kinase, which phosphorylates beta ARs in vitro in an agonist-dependent
manner. This kinase is inhibited by two classes of compounds, polyanions
and synthetic peptides derived from the beta 2-adrenergic receptor
(beta 2AR). In this report we describe the effects of these inhibitors
on the process of homologous desensitization induced by the beta-adrenergic
agonist isoproterenol. Permeabilization of human epidermoid carcinoma
A431 cells with digitonin was used to permit access of the charged
inhibitors to the cytosol; this procedure did not interfere with
the pattern of isoproterenol-induced homologous desensitization of
beta 2AR-stimulated adenylyl cyclase. Inhibitors of beta AR kinase
markedly inhibited homologous desensitization of beta 2ARs in the
permeabilized cells. Inhibition of desensitization by heparin, the
most potent of the polyanion inhibitors of beta AR kinase, occurred
over the same concentration range (5-50 nM) as inhibition of purified
beta AR kinase assessed in a reconstituted system. Inhibition of
desensitization by heparin was accompanied by a marked reduction
of receptor phosphorylation in the permeabilized cells. Whereas inhibitors
of beta AR kinase inhibited homologous desensitization, inhibitors
of protein kinase C and of cyclic-nucleotide-dependent protein kinases
were ineffective. These data establish that phosphorylation of beta
ARs by beta AR kinase is an essential step in homologous desensitization
of the receptors. They further suggest a potential therapeutic value
of inhibitors of beta AR kinase in inhibiting agonist-induced desensitization.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Lohse, M. J. and Lefkowitz, R. J. and Caron, M. G. and Benovic, J. L.},
biburl = {https://www.bibsonomy.org/bibtex/2814538f9eff284cb2dacd309bddc3f33/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {f134ed2785674ffbee8dd358a38a2d5d},
intrahash = {814538f9eff284cb2dacd309bddc3f33},
issn = {0027-8424 (Print) 0027-8424 (Linking)},
journal = {Proc Natl Acad Sci U S A},
keywords = {*Protein Animals Cell Cricetinae Cultured Digitonin Drug Heparin/pharmacology Humans Inhibitors Isoproterenol/pharmacology Kinase Kinetics Lung/analysis Membrane Permeability Phosphorylation Tolerance Tumor beta/drug effects/*metabolism Receptor Adrenergic},
month = May,
note = {Lohse, M J Lefkowitz, R J Caron, M G Benovic, J L Comparative Study
Research Support, Non-U.S. Gov't United states Proceedings of the
National Academy of Sciences of the United States of America Proc
Natl Acad Sci U S A. 1989 May;86(9):3011-5.},
number = 9,
pages = {3011-5},
shorttitle = {Inhibition of beta-adrenergic receptor kinase prevents rapid homologous
desensitization of beta 2-adrenergic receptors},
timestamp = {2010-12-14T18:22:41.000+0100},
title = {Inhibition of beta-adrenergic receptor kinase prevents rapid homologous
desensitization of beta 2-adrenergic receptors},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2541428},
volume = 86,
year = 1989
}