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Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus
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| Zeitschriftentitel: | Proceedings of the National Academy of Sciences |
|---|---|
| Personen und Körperschaften: | , , , |
| In: | Proceedings of the National Academy of Sciences, 98, 2001, 1, S. 93-98 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Proceedings of the National Academy of Sciences
|
| Schlagwörter: |
| author_facet |
Barak, Larry S. Oakley, Robert H. Laporte, Stéphane A. Caron, Marc G. Barak, Larry S. Oakley, Robert H. Laporte, Stéphane A. Caron, Marc G. |
|---|---|
| author |
Barak, Larry S. Oakley, Robert H. Laporte, Stéphane A. Caron, Marc G. |
| spellingShingle |
Barak, Larry S. Oakley, Robert H. Laporte, Stéphane A. Caron, Marc G. Proceedings of the National Academy of Sciences Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus Multidisciplinary |
| author_sort |
barak, larry s. |
| spelling |
Barak, Larry S. Oakley, Robert H. Laporte, Stéphane A. Caron, Marc G. 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.98.1.93 <jats:p>Agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCR) are mediated by the binding of arrestins to phosphorylated receptors. The affinity of arrestins for the phosphorylated GPCR regulates the ability of the internalized receptor to be dephosphorylated and recycled back to the plasma membrane. In this study, we show that the naturally occurring loss of function vasopressin receptor mutation R137H, which is associated with familial nephrogenic diabetes insipidus, induces constitutive arrestin-mediated desensitization. In contrast to the wild-type vasopressin receptor, the nonsignaling R137H receptor is phosphorylated and sequestered in arrestin-associated intracellular vesicles even in the absence of agonist. Eliminating molecular determinants on the receptor that promote high affinity arrestin–receptor interaction reestablishes plasma membrane localization and the ability of the mutated receptors to signal. These findings suggest that unregulated desensitization can contribute to the etiology of a GPCR-based disease, implying that pharmacological targeting of GPCR desensitization may be therapeutically beneficial.</jats:p> Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus Proceedings of the National Academy of Sciences |
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Proceedings of the National Academy of Sciences, 2001 |
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| title |
Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| title_unstemmed |
Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| title_full |
Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| title_fullStr |
Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| title_full_unstemmed |
Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| title_short |
Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| title_sort |
constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| topic |
Multidisciplinary |
| url |
http://dx.doi.org/10.1073/pnas.98.1.93 |
| publishDate |
2001 |
| physical |
93-98 |
| description |
<jats:p>Agonist-dependent desensitization and internalization of G
protein-coupled receptors (GPCR) are mediated by the binding of
arrestins to phosphorylated receptors. The affinity of arrestins for
the phosphorylated GPCR regulates the ability of the internalized
receptor to be dephosphorylated and recycled back to the plasma
membrane. In this study, we show that the naturally occurring loss
of function vasopressin receptor mutation R137H, which is associated
with familial nephrogenic diabetes insipidus, induces constitutive
arrestin-mediated desensitization. In contrast to the wild-type
vasopressin receptor, the nonsignaling R137H receptor is phosphorylated
and sequestered in arrestin-associated intracellular vesicles even in
the absence of agonist. Eliminating molecular determinants on the
receptor that promote high affinity arrestin–receptor interaction
reestablishes plasma membrane localization and the ability of the
mutated receptors to signal. These findings suggest that unregulated
desensitization can contribute to the etiology of a GPCR-based disease,
implying that pharmacological targeting of GPCR desensitization may be
therapeutically beneficial.</jats:p> |
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| author | Barak, Larry S., Oakley, Robert H., Laporte, Stéphane A., Caron, Marc G. |
| author_facet | Barak, Larry S., Oakley, Robert H., Laporte, Stéphane A., Caron, Marc G., Barak, Larry S., Oakley, Robert H., Laporte, Stéphane A., Caron, Marc G. |
| author_sort | barak, larry s. |
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| container_title | Proceedings of the National Academy of Sciences |
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| description | <jats:p>Agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCR) are mediated by the binding of arrestins to phosphorylated receptors. The affinity of arrestins for the phosphorylated GPCR regulates the ability of the internalized receptor to be dephosphorylated and recycled back to the plasma membrane. In this study, we show that the naturally occurring loss of function vasopressin receptor mutation R137H, which is associated with familial nephrogenic diabetes insipidus, induces constitutive arrestin-mediated desensitization. In contrast to the wild-type vasopressin receptor, the nonsignaling R137H receptor is phosphorylated and sequestered in arrestin-associated intracellular vesicles even in the absence of agonist. Eliminating molecular determinants on the receptor that promote high affinity arrestin–receptor interaction reestablishes plasma membrane localization and the ability of the mutated receptors to signal. These findings suggest that unregulated desensitization can contribute to the etiology of a GPCR-based disease, implying that pharmacological targeting of GPCR desensitization may be therapeutically beneficial.</jats:p> |
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| imprint | Proceedings of the National Academy of Sciences, 2001 |
| imprint_str_mv | Proceedings of the National Academy of Sciences, 2001 |
| institution | DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14 |
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| mega_collection | Proceedings of the National Academy of Sciences (CrossRef) |
| physical | 93-98 |
| publishDate | 2001 |
| publishDateSort | 2001 |
| publisher | Proceedings of the National Academy of Sciences |
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| series | Proceedings of the National Academy of Sciences |
| source_id | 49 |
| spelling | Barak, Larry S. Oakley, Robert H. Laporte, Stéphane A. Caron, Marc G. 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.98.1.93 <jats:p>Agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCR) are mediated by the binding of arrestins to phosphorylated receptors. The affinity of arrestins for the phosphorylated GPCR regulates the ability of the internalized receptor to be dephosphorylated and recycled back to the plasma membrane. In this study, we show that the naturally occurring loss of function vasopressin receptor mutation R137H, which is associated with familial nephrogenic diabetes insipidus, induces constitutive arrestin-mediated desensitization. In contrast to the wild-type vasopressin receptor, the nonsignaling R137H receptor is phosphorylated and sequestered in arrestin-associated intracellular vesicles even in the absence of agonist. Eliminating molecular determinants on the receptor that promote high affinity arrestin–receptor interaction reestablishes plasma membrane localization and the ability of the mutated receptors to signal. These findings suggest that unregulated desensitization can contribute to the etiology of a GPCR-based disease, implying that pharmacological targeting of GPCR desensitization may be therapeutically beneficial.</jats:p> Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus Proceedings of the National Academy of Sciences |
| spellingShingle | Barak, Larry S., Oakley, Robert H., Laporte, Stéphane A., Caron, Marc G., Proceedings of the National Academy of Sciences, Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus, Multidisciplinary |
| title | Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| title_full | Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| title_fullStr | Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| title_full_unstemmed | Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| title_short | Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| title_sort | constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| title_unstemmed | Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus |
| topic | Multidisciplinary |
| url | http://dx.doi.org/10.1073/pnas.98.1.93 |