Differential beta-arrestin trafficking and endosomal sorting of somatostatin receptor subtypes.

The physiological responses of somatostatin are mediated
by five different G protein-coupled receptors. Although
agonist-induced endocytosis of the various somatostatin
receptor subtypes (sst1–sst5) has been
studied in detail, little is known about their postendocytic
trafficking. Here we show that somatostatin receptors
profoundly differ in patterns of -arrestin mobilization
and endosomal sorting. The -arrestin-dependent
trafficking of the sst2A somatostatin receptor resembled
that of a class B receptor in that upon receptor activation,
-arrestin and the receptor formed stable complexes
and internalized together into the same endocytic
vesicles. This pattern was dependent on GRK2 (G
protein-coupled receptor kinase 2)-mediated phosphorylation
of a cluster of phosphate acceptor sites within
the cytoplasmic tail of the sst2A receptor. Unlike other
class B receptors, however, the sst2A receptor was rapidly
resensitized and recycled to the plasma membrane.
The -arrestin mobilization of the sst3 and the sst5 somatostatin
receptors resembled that of a class A receptor
in that upon receptor activation, -arrestin and the
receptor formed relatively unstable complexes that dissociated
at or near the plasma membrane. Consequently,
-arrestin was excluded from sst3-containing
vesicles. Unlike other class A receptors, a large proportion
of sst3 receptors was subject to ubiquitin-dependent
lysosomal degradation and did not rapidly recycle to
the plasma membrane. The sst4 somatostatin receptor is
unique in that it did not exhibit agonist-dependent receptor
phosphorylation and -arrestin recruitment. Together,
these findings may provide important clues
about the regulation of receptor responsiveness during
long-term administration of somatostatin analogs