Differential S-palmitoylation of the human and rodent ß3-adrenergic receptors.
J Biol Chem
; 294(7): 2569-2578, 2019 02 15.
Article
em En
| MEDLINE
| ID: mdl-30541923
ABSTRACT
With few reported exceptions, G protein-coupled receptors (GPCRs) are modified by Cys palmitoylation (S-palmitoylation). In multiple GPCRs, S-palmitoylation targets a canonical site within the C-terminal cytoplasmic tail adjacent to the C terminus of the seventh transmembrane domain, but modification of additional sites is exemplified by the ß-adrenergic receptors (ßARs). The ß1AR is S-palmitoylated at a second, more distal site within the C-terminal tail, and the ß2AR is modified at a second site within the third intracellular loop, neither of which is conserved in other ßAR isoforms. The functional roles of S-palmitoylation of disparate sites are incompletely characterized for any GPCR family. Here, we describe S-palmitoylation of the ß3AR. We compared mouse and human ß3ARs and found that both were S-palmitoylated at the canonical site within the C-terminal tail, Cys-358 and Cys-361/363 in mouse and human ß3ARs, respectively. Surprisingly, the human ß3AR was S-palmitoylated at two additional sites, Cys-153 and Cys-292 within the second and third intracellular loops, respectively. Cys-153 is apparently unique to the human ß3AR, and Cys-292 is conserved primarily in primates. Mutational substitution of C-tail Cys in human but not mouse ß3ARs resulted in diminished ligand-induced cAMP production. Substitution of Cys-153, Cys-292, or Cys-361/363 within the human ß3AR diminished membrane-receptor abundance, but only Cys-361/363 substitution diminished membrane-receptor half-life. Thus, S-palmitoylation of different sites differentially regulates the human ß3AR, and differential S-palmitoylation distinguishes human and rodent ß3ARs, potentially contributing to species-specific differences in the clinical efficacy of ß3AR-directed pharmacological approaches to disease.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores Adrenérgicos beta 3
/
Lipoilação
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article