Changes in G protein-coupled receptor sorting protein affinity regulate postendocytic targeting of G protein-coupled receptors.
After activation, most G protein-coupled receptors (GPCRs) are regulated by a cascade of events involving desensitization and endocytosis. Internalized receptors can then be recycled to the plasma membrane, retained in an endosomal compartment, or targeted for degradation. The GPCR-associated sorting protein, GASP, has been shown to preferentially sort a number of native GPCRs to the lysosome for degradation after endocytosis. Here we show that a mutant beta(2) adrenergic receptor and a mutant mu opioid receptor that have previously been described as lacking "recycling signals" due to mutations in their C termini in fact bind to GASP and are targeted for degradation. We also show that a mutant dopamine D1 receptor, which has likewise been described as lacking a recycling signal, does not bind to GASP and is therefore not targeted for degradation. Together, these results indicate that alteration of receptors in their C termini can expose determinants with affinity for GASP binding and consequently target receptors for degradation.
Thompson
Dawn
D
Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, California 94608, USA.
Pusch
Margareta
M
Whistler
Jennifer L
JL
D001710:Biotin / Q000737:chemistry; D002460:Cell Line; D004705:Endocytosis; D005786:Gene Expression Regulation; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics; D015398:Signal Transduction; D014168:Transferrin / Q000378:metabolism
D018343:Receptors, Adrenergic, beta-2; D017447:Receptors, Dopamine D1; D043562:Receptors, G-Protein-Coupled; D017450:Receptors, Opioid, mu; D014168:Transferrin; D001710:Biotin