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J. Biol. Chem., Vol. 277, Issue 7, 4618-4627, February 15, 2002
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From the Department of Physiology, Tulane University School of
Medicine and Health Sciences Center, New Orleans, Louisiana
70112
We examined the kinetics of internalization,
trafficking, and down-regulation of recombinant guanylyl
cyclase/natriuretic peptide receptor-A (NPRA) utilizing stably
transfected 293 cells expressing a very high density of receptors.
After atrial natriuretic peptide (ANP) binding to NPRA, ligand-receptor
complexes are internalized, processed intracellularly, and sequestered
into subcellular compartments, which provided an approach to examining
directly the dynamics of metabolic turnover of NPRA in intact cells.
The translocation of ligand-receptor complexes from cell surface to
intracellular compartments seems to be linked to
ANP-dependent down-regulation of NPRA. Using tryptic
proteolysis of cell surface receptors, it was found that ~40-50% of
internalized ligand-receptor complexes recycled back to the plasma
membrane with an apparent t1/2 = 8 min. The
recycling of NPRA was blocked by the lysosomotropic agent chloroquine,
the energy depleter dinitrophenol, and also by low temperature,
suggesting that recycling of the receptor is an energy- and
temperature-dependent process. Data suggest that
~70-80% of internalized 125I-ANP is processed through a
lysosomal degradative pathway; however, 20-25% of internalized ligand
is released intact into the cell exterior through an alternative
mechanism involving an chloroquine-insensitive pathway. It is implied
that internalization and processing of bound ANP-NPRA complexes
may play an important role in mediating the biological action of
hormone and the receptor protein. In retrospect, this could occur at
the level of receptor regulation or through the initiation of ANP
mediated signals. It is envisioned that the endocytotic pathway of
ligand-receptor complexes of ANP-NPRA would lead to termination and/or
diminished responsiveness of ANP in target cells.
Ligand-regulated Internalization, Trafficking, and
Down-regulation of Guanylyl Cyclase/Atrial Natriuretic Peptide
Receptor-A in Human Embryonic Kidney 293 Cells*
,
*
This work was supported by the National Institutes of Health
Grant HL 57531.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Physiology
SL39, Tulane University School of Medicine and Health Sciences Center,
1430 Tulane Ave., New Orleans, LA 70112. Tel.: 504-584-1628; Fax:
504-584-2675; E-mail: kpandey@tulane.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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