The Journal of Neuroscience, March 15, 2003, 23(6):2075
Neurotrophin-Regulated Sorting of Opioid Receptors in the
Biosynthetic Pathway of Neurosecretory Cells
Kyung-Ah
Kim and
Mark
von
Zastrow
Departments of Psychiatry and Cellular and Molecular Pharmacology,
University of California, San Francisco School of Medicine, San
Francisco, California 94143-0984
Neurotrophins modulate the endogenous opioid system, but the
underlying mechanisms are poorly understood. We observed an unexpected effect of neurotrophin signaling on the membrane trafficking of recombinant opioid receptors expressed in neurosecretory cells. Epitope-tagged 
opioid receptor (DOR) and µ opioid receptor (MOR) were differentially localized between surface and internal membrane pools, respectively, when expressed in primary cultured hippocampal neurons, consistent with previous studies by others of natively expressing neurons. Selective intracellular targeting of DOR was observed in nerve growth factor (NGF)-differentiated PC12
neurosecretory cells but not in PC12 cells cultured in the absence of
NGF, where both DOR and MOR were localized in the plasma membrane.
Surprisingly, NGF initiated intracellular targeting of DOR in PC12
cells acutely, within 60 min after initial activation of TrkA. The
NGF-induced intracellular pool of DOR originated from a late stage of
the biosynthetic pathway after exit from the endoplasmic reticulum and
processing of N-linked glycans in the Golgi, resulting in the
accumulation in cells of a biochemically mature "reserve" pool of
intracellular DOR that exhibited depolarization-dependent insertion
into the plasma membrane. The C-terminal cytoplasmic tail of DOR
contains a signal determining the specificity of NGF-regulated intracellular targeting. These results indicate that cloned opioid receptors are differentially targeted when expressed heterologously in
neurosecretory cells, establish a model system that facilitates mechanistic study of this process, and suggest a novel function of
neurotrophins in modulating the anterograde membrane trafficking of
opioid receptors.
Key words:
opioid; membrane trafficking; regulation; neurotrophin; exocytosis; plasticity
Copyright © 2003 Society for Neuroscience 0270-6474/03/2362075-11$05.00/0
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