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Synthetic peptides of the hamster beta 2‐adrenoceptor as substrates and inhibitors of the beta‐adrenoceptor kinase.
Author(s) -
Benovic JL,
Onorato J.,
Lohse MJ,
Dohlman HG,
Staniszewski C.,
Caron MG,
Lefkowitz RJ
Publication year - 1990
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.1990.tb05462.x
Subject(s) - beta adrenergic receptor kinase , homologous desensitization , beta (programming language) , receptor , kinase , g protein coupled receptor kinase , biochemistry , protein kinase c , beta 1 adrenergic receptor , biology , adrenergic receptor , agonist , chemistry , g protein coupled receptor , computer science , programming language
1. The beta‐adrenoceptor is one of a number of G protein‐coupled receptors which have been proposed to contain seven transmembrane alpha‐ helices. The function of this receptor appears to be regulated by phosphorylation by a specific enzyme, the beta‐adrenoceptor kinase. Synthetic peptides which comprise each of the proposed intra‐ and extracellular domains of the beta 2‐adrenoceptor have been tested as potential substrates and inhibitors of the beta‐adrenoceptor kinase. 2. Two peptides which encompass the middle and terminal portions of the carboxyl tail of the receptor served as substrates by beta‐adrenoceptor kinase. The kinetics of the phosphorylation reaction, however, suggest that these peptides are 10(6)‐fold poorer substrate than the agonist occupied receptor. 3. A number of synthetic peptides also served as inhibitors of beta 2‐adrenoceptor phosphorylation by beta‐adrenoceptor kinase. In particular, a peptide which comprised the first intracellular loop of the beta 2‐adrenoceptor (amino acids 56‐74) inhibited most effectively with an IC50 of 40 microM. 4. These results suggest that multiple intracellular regions of the beta‐receptor may serve as potential sites of interaction with beta‐adrenoceptor kinase. Moreover, these regions may serve as potential targets for the development of specific inhibitors of beta‐adrenoceptor kinase which could be used to block homologous desensitization.