Mechanisms of endothelin receptor subtype-specific targeting to distinct intracellular trafficking pathways

作者：Paasche JD; Attramadal T; Sandberg C; Johansen HK; Attramadal H^*

来源：Journal of Biological Chemistry, 2001, 276(36): 34041-34050.

DOI：10.1074/jbc.M103243200

We recently reported that the endothelin (ET) receptor subtypes ETA and ETB are targeted to distinct intracellular destinations upon agonist stimulation (Bremnes, T., Paasche, J. D., Mehlum, A., Sandberg, C., Bremnes, B., and Attramadal, H. (2000) J. Biol. Chem. 275, 17596-17604). The ETA receptor was shown to follow the recycling route of transferrin, whereas ETB is targeted to lysosomes for degradation. In the present study we have investigated the mechanisms of ET receptor subtype-specific targeting to distinct intracellular trafficking pathways. Truncation mutants of the ETA and ETB receptors with deletions of the cytoplasmic carboxyl-terminal tail distal to the palmitoylation site were found to mediate inositol phosphate accumulation and to internalize upon agonist stimulation, although internalization occurred at a slower rate as compared with the wild-type receptors. However, the truncated ETA receptor was no longer able to undergo recycling. Rather, both truncation mutants were recognized by beta -arrestin for recruitment to endocytosis and were sorted to lysosomes by a dynamin-dependent internalization pathway. Furthermore, studies of chimeric ETA and ETB receptors where the cytoplasmic tail of ETA was swapped with the corresponding domain of ETB, and vice versa, revealed that the cytoplasmic tail of ETB is required for efficient lysosomal sorting and that signals for targeting to recycling reside in the cytoplasmic tail of the ETA receptor.

• 出版日期2001-9-7