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Montreal Neurological Institute, McGill University (D.N., M.H., A.B.), Montreal, Quebec, Canada H3A 2B4; Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice-Sophia Antipolis (G.G, J.-P.V., J.M.), Valbonne, France; and the Department of Pharmacology, University of Pennsylvania School of Medicine (T.R.), Philadelphia, Pennsylvania 19104
Address all correspondence and requests for reprints to: Dr. Alain Beaudet, Department of Neurobiology, McGill University, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada H3A 2B4. E-mail: MCIN{at}MUSICA.MCGILL.CA
A growing body of evidence suggests that neuropeptide binding to G
protein-linked receptors may result in internalization of
receptor-ligand complexes, followed by intracellular mobilization and
degradation of the ligand into its target cells. Because of discrepant
results in the literature concerning the occurrence of such a mechanism
for the tetradecapeptide somatostatin (SRIF), we have reinvestigated
this question by comparing the binding and internalization of iodinated
and fluorescent derivatives of the metabolically stable analog of SRIF,
[D-Trp8]SRIF, in COS-7 cells transfected
with complementary DNA encoding the sst1 or
sst2A receptor subtype. A series of fluoresceinyl and
Bodipy fluorescent derivatives of
[D-Trp8]SRIF-14 was purified by HPLC,
analyzed for purity by mass spectrometry, and tested for biological
activity in a membrane binding assay. Of the six compounds tested,
fluoresceinyl and Bodipy derivatives labeled in position 
(fluo-SRIF) retained high affinity for SRIF receptors. COS-7 cells
transfected with complementary DNA encoding either sst1 or
sst2A receptors both displayed specific, high affinity
binding of iodinated and fluo-SRIF. At 4 C, the labeling was confined
to the cell surface in both cell types, as indicated by the fact that
it was entirely removable by a hypertonic acid wash and assumed a
pericellular distribution in the confocal microscope. At 37 C, the fate
of specifically bound ligand varied markedly according to the type of
receptor transfected. In cells encoding the sst1 receptor,
approximately 20% of specifically bound ligand was recovered in the
acid-resistant (i.e. intracellular) fraction. This
fraction remained clustered at the periphery of the cell, suggesting
that it was being sequestered either within or immediately beneath the
plasma membrane. By contrast, in cells transfected with
sst2A receptors, up to 75% of specifically bound ligand
was recovered inside the cells, where it clustered into small
endosome-like particles. These particles increased in size and moved
toward the nucleus with time, suggestive of receptor-ligand complexes
proceeding down the endocytic pathway. These results demonstrate that
neuropeptides may be processed differently depending on the subtype of
receptor expressed in their target cells and suggest that these
different processing patterns may reflect different modes of
sensitization/desensitization and recycling of the receptors, and
thereby of transmembrane signaling.
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