Differential S-palmitoylation of the human and rodent ?3-adrenergic receptors.

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 ?-adrenergic receptors (?ARs). The ?1AR is S-palmitoylated at a second, more distal site within the C-terminal tail, and the ?2AR is modified at a second site within the third intracellular loop, neither of which is conserved in other ?AR isoforms. The functional roles of S-palmitoylation of disparate sites are incompletely characterized for any GPCR family. Here, we describe S-palmitoylation of the ?3AR. We compared mouse and human ?3ARs 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 ?3ARs, respectively. Surprisingly, the human ?3AR 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 ?3AR, and Cys-292 is conserved primarily in primates. Mutational substitution of C-tail Cys in human but not mouse ?3ARs resulted in diminished ligand-induced cAMP production. Substitution of Cys-153, Cys-292, or Cys-361/363 within the human ?3AR 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 ?3AR, and differential S-palmitoylation distinguishes human and rodent ?3ARs, potentially contributing to species-specific differences in the clinical efficacy of ?3AR-directed pharmacological approaches to disease.

SUBMITTER: Adachi N 

PROVIDER: S-EPMC6378987 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature