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(Received for publication, October 25, 1996, and in revised form, January 30, 1997)
From the Cellular responsiveness to the inhibitory peptide
somatostatin (SRIF) or its clinically used analogs can desensitize with agonist exposure. While desensitization of other seven-transmembrane domain receptors is mediated by receptor phosphorylation and/or internalization, the mechanisms mediating SRIF receptor (sst) desensitization are unknown. Therefore, we investigated the
susceptibility of the sst2A receptor isotype to ligand-induced
desensitization, internalization, and phosphorylation in GH-R2 cells, a
clone of pituitary tumor cells overexpressing this receptor. A 30-min
exposure of cells to either SRIF or the analog SMS 201-995 (SMS)
reduced both the potency and efficacy of agonist inhibition of adenylyl cyclase. Internalization of receptor-bound ligand was rapid
(t1/2 = 4 min) and
temperature-dependent. SRIF and SMS increased the phosphorylation of the 71-kDa sst2A protein 25-fold within 15 min.
Receptor phosphorylation was dependent on both the concentration and
time of agonist exposure and was not affected by pertussis toxin
pretreatment, indicating that receptor occupancy rather than second
messenger formation was required. Receptor phosphorylation was also
stimulated by phorbol 12-myristate 13-acetate activation of protein
kinase C. Both ligand-stimulated and phorbol 12-myristate 13-acetate-stimulated receptor phosphorylation occurred primarily on
serine. These studies are the first demonstration of
agonist-dependent desensitization, internalization, and
phosphorylation of the sst2A receptor and suggest that phosphorylation
may mediate the homologous and heterologous regulation of this
receptor.
Volume 272, Number 21,
Issue of May 23, 1997
pp. 13869-13876
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
,
Department of Pharmacology, University of
Texas Medical School, Houston, Texas 77225 and the
¶ Agricultural Research Center, American Cyanamid Co.,
Princeton, New Jersey 08543
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