The Experts below are selected from a list of 81 Experts worldwide ranked by ideXlab platform
Lakshmi A Devi - One of the best experts on this subject based on the ideXlab platform.
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thr located within the cooh terminal tail of the opiate receptor is involved in receptor down Regulation
Journal of Biological Chemistry, 1996Co-Authors: Svetlana Cvejic, Nino Trapaidze, Curt Cyr, Lakshmi A DeviAbstract:Abstract Prolonged exposure to abused drugs such as opiates causes decreased response to the drug; this reduced sensitivity is thought to be due to the loss of receptors, or down-Regulation. The molecular mechanism of the opiate receptor down-Regulation is not known. In order to address this, we generated a number of mutants of the opiate receptor COOH-terminal tail. When expressed in the Chinese hamster ovary cells, both the wild type and the receptor with a deletion of 37 COOH-terminal residues bind diprenorphine with comparable affinities and show similar decreases in cAMP levels in response to D-Ala2, D-Leu5, enkephalin (DADLE). However, the truncated receptor does not show down-Regulation from the cell surface upon prolonged exposure (2-48 h) to DADLE. In contrast, both the wild type receptor and the receptor with the deletion of only 15 COOH-terminal residues show substantial down-Regulation upon long term DADLE treatment. These results suggest that the region located between 15 and 37 residues from the COOH terminus is involved in the receptor down-Regulation. In order to identify residues that play a key role in down-Regulation, Point mutations of residues within this region were examined for their ability to modulate receptor down-Regulation. The receptor with a mutation of Thr to Ala does not down-regulate, whereas the receptor with a mutation of Ser to Gly down-regulates with a time course similar to that of the wild type receptor. Taken together, these results suggest that the COOH-terminal tail is not essential for functional coupling but is necessary for down-Regulation and that Thr is critical for the agonist-mediated down-Regulation of the opiate receptor.
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Thr353, Located within the COOH-terminal Tail of the ´ Opiate Receptor, Is Involved in Receptor Down-Regulation
The Journal of biological chemistry, 1996Co-Authors: Svetlana Cvejic, Nino Trapaidze, Curt Cyr, Lakshmi A DeviAbstract:Abstract Prolonged exposure to abused drugs such as opiates causes decreased response to the drug; this reduced sensitivity is thought to be due to the loss of receptors, or down-Regulation. The molecular mechanism of the opiate receptor down-Regulation is not known. In order to address this, we generated a number of mutants of the opiate receptor COOH-terminal tail. When expressed in the Chinese hamster ovary cells, both the wild type and the receptor with a deletion of 37 COOH-terminal residues bind diprenorphine with comparable affinities and show similar decreases in cAMP levels in response to D-Ala2, D-Leu5, enkephalin (DADLE). However, the truncated receptor does not show down-Regulation from the cell surface upon prolonged exposure (2-48 h) to DADLE. In contrast, both the wild type receptor and the receptor with the deletion of only 15 COOH-terminal residues show substantial down-Regulation upon long term DADLE treatment. These results suggest that the region located between 15 and 37 residues from the COOH terminus is involved in the receptor down-Regulation. In order to identify residues that play a key role in down-Regulation, Point mutations of residues within this region were examined for their ability to modulate receptor down-Regulation. The receptor with a mutation of Thr to Ala does not down-regulate, whereas the receptor with a mutation of Ser to Gly down-regulates with a time course similar to that of the wild type receptor. Taken together, these results suggest that the COOH-terminal tail is not essential for functional coupling but is necessary for down-Regulation and that Thr is critical for the agonist-mediated down-Regulation of the opiate receptor.
Svetlana Cvejic - One of the best experts on this subject based on the ideXlab platform.
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thr located within the cooh terminal tail of the opiate receptor is involved in receptor down Regulation
Journal of Biological Chemistry, 1996Co-Authors: Svetlana Cvejic, Nino Trapaidze, Curt Cyr, Lakshmi A DeviAbstract:Abstract Prolonged exposure to abused drugs such as opiates causes decreased response to the drug; this reduced sensitivity is thought to be due to the loss of receptors, or down-Regulation. The molecular mechanism of the opiate receptor down-Regulation is not known. In order to address this, we generated a number of mutants of the opiate receptor COOH-terminal tail. When expressed in the Chinese hamster ovary cells, both the wild type and the receptor with a deletion of 37 COOH-terminal residues bind diprenorphine with comparable affinities and show similar decreases in cAMP levels in response to D-Ala2, D-Leu5, enkephalin (DADLE). However, the truncated receptor does not show down-Regulation from the cell surface upon prolonged exposure (2-48 h) to DADLE. In contrast, both the wild type receptor and the receptor with the deletion of only 15 COOH-terminal residues show substantial down-Regulation upon long term DADLE treatment. These results suggest that the region located between 15 and 37 residues from the COOH terminus is involved in the receptor down-Regulation. In order to identify residues that play a key role in down-Regulation, Point mutations of residues within this region were examined for their ability to modulate receptor down-Regulation. The receptor with a mutation of Thr to Ala does not down-regulate, whereas the receptor with a mutation of Ser to Gly down-regulates with a time course similar to that of the wild type receptor. Taken together, these results suggest that the COOH-terminal tail is not essential for functional coupling but is necessary for down-Regulation and that Thr is critical for the agonist-mediated down-Regulation of the opiate receptor.
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Thr353, Located within the COOH-terminal Tail of the ´ Opiate Receptor, Is Involved in Receptor Down-Regulation
The Journal of biological chemistry, 1996Co-Authors: Svetlana Cvejic, Nino Trapaidze, Curt Cyr, Lakshmi A DeviAbstract:Abstract Prolonged exposure to abused drugs such as opiates causes decreased response to the drug; this reduced sensitivity is thought to be due to the loss of receptors, or down-Regulation. The molecular mechanism of the opiate receptor down-Regulation is not known. In order to address this, we generated a number of mutants of the opiate receptor COOH-terminal tail. When expressed in the Chinese hamster ovary cells, both the wild type and the receptor with a deletion of 37 COOH-terminal residues bind diprenorphine with comparable affinities and show similar decreases in cAMP levels in response to D-Ala2, D-Leu5, enkephalin (DADLE). However, the truncated receptor does not show down-Regulation from the cell surface upon prolonged exposure (2-48 h) to DADLE. In contrast, both the wild type receptor and the receptor with the deletion of only 15 COOH-terminal residues show substantial down-Regulation upon long term DADLE treatment. These results suggest that the region located between 15 and 37 residues from the COOH terminus is involved in the receptor down-Regulation. In order to identify residues that play a key role in down-Regulation, Point mutations of residues within this region were examined for their ability to modulate receptor down-Regulation. The receptor with a mutation of Thr to Ala does not down-regulate, whereas the receptor with a mutation of Ser to Gly down-regulates with a time course similar to that of the wild type receptor. Taken together, these results suggest that the COOH-terminal tail is not essential for functional coupling but is necessary for down-Regulation and that Thr is critical for the agonist-mediated down-Regulation of the opiate receptor.
Curt Cyr - One of the best experts on this subject based on the ideXlab platform.
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thr located within the cooh terminal tail of the opiate receptor is involved in receptor down Regulation
Journal of Biological Chemistry, 1996Co-Authors: Svetlana Cvejic, Nino Trapaidze, Curt Cyr, Lakshmi A DeviAbstract:Abstract Prolonged exposure to abused drugs such as opiates causes decreased response to the drug; this reduced sensitivity is thought to be due to the loss of receptors, or down-Regulation. The molecular mechanism of the opiate receptor down-Regulation is not known. In order to address this, we generated a number of mutants of the opiate receptor COOH-terminal tail. When expressed in the Chinese hamster ovary cells, both the wild type and the receptor with a deletion of 37 COOH-terminal residues bind diprenorphine with comparable affinities and show similar decreases in cAMP levels in response to D-Ala2, D-Leu5, enkephalin (DADLE). However, the truncated receptor does not show down-Regulation from the cell surface upon prolonged exposure (2-48 h) to DADLE. In contrast, both the wild type receptor and the receptor with the deletion of only 15 COOH-terminal residues show substantial down-Regulation upon long term DADLE treatment. These results suggest that the region located between 15 and 37 residues from the COOH terminus is involved in the receptor down-Regulation. In order to identify residues that play a key role in down-Regulation, Point mutations of residues within this region were examined for their ability to modulate receptor down-Regulation. The receptor with a mutation of Thr to Ala does not down-regulate, whereas the receptor with a mutation of Ser to Gly down-regulates with a time course similar to that of the wild type receptor. Taken together, these results suggest that the COOH-terminal tail is not essential for functional coupling but is necessary for down-Regulation and that Thr is critical for the agonist-mediated down-Regulation of the opiate receptor.
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Thr353, Located within the COOH-terminal Tail of the ´ Opiate Receptor, Is Involved in Receptor Down-Regulation
The Journal of biological chemistry, 1996Co-Authors: Svetlana Cvejic, Nino Trapaidze, Curt Cyr, Lakshmi A DeviAbstract:Abstract Prolonged exposure to abused drugs such as opiates causes decreased response to the drug; this reduced sensitivity is thought to be due to the loss of receptors, or down-Regulation. The molecular mechanism of the opiate receptor down-Regulation is not known. In order to address this, we generated a number of mutants of the opiate receptor COOH-terminal tail. When expressed in the Chinese hamster ovary cells, both the wild type and the receptor with a deletion of 37 COOH-terminal residues bind diprenorphine with comparable affinities and show similar decreases in cAMP levels in response to D-Ala2, D-Leu5, enkephalin (DADLE). However, the truncated receptor does not show down-Regulation from the cell surface upon prolonged exposure (2-48 h) to DADLE. In contrast, both the wild type receptor and the receptor with the deletion of only 15 COOH-terminal residues show substantial down-Regulation upon long term DADLE treatment. These results suggest that the region located between 15 and 37 residues from the COOH terminus is involved in the receptor down-Regulation. In order to identify residues that play a key role in down-Regulation, Point mutations of residues within this region were examined for their ability to modulate receptor down-Regulation. The receptor with a mutation of Thr to Ala does not down-regulate, whereas the receptor with a mutation of Ser to Gly down-regulates with a time course similar to that of the wild type receptor. Taken together, these results suggest that the COOH-terminal tail is not essential for functional coupling but is necessary for down-Regulation and that Thr is critical for the agonist-mediated down-Regulation of the opiate receptor.
Nino Trapaidze - One of the best experts on this subject based on the ideXlab platform.
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thr located within the cooh terminal tail of the opiate receptor is involved in receptor down Regulation
Journal of Biological Chemistry, 1996Co-Authors: Svetlana Cvejic, Nino Trapaidze, Curt Cyr, Lakshmi A DeviAbstract:Abstract Prolonged exposure to abused drugs such as opiates causes decreased response to the drug; this reduced sensitivity is thought to be due to the loss of receptors, or down-Regulation. The molecular mechanism of the opiate receptor down-Regulation is not known. In order to address this, we generated a number of mutants of the opiate receptor COOH-terminal tail. When expressed in the Chinese hamster ovary cells, both the wild type and the receptor with a deletion of 37 COOH-terminal residues bind diprenorphine with comparable affinities and show similar decreases in cAMP levels in response to D-Ala2, D-Leu5, enkephalin (DADLE). However, the truncated receptor does not show down-Regulation from the cell surface upon prolonged exposure (2-48 h) to DADLE. In contrast, both the wild type receptor and the receptor with the deletion of only 15 COOH-terminal residues show substantial down-Regulation upon long term DADLE treatment. These results suggest that the region located between 15 and 37 residues from the COOH terminus is involved in the receptor down-Regulation. In order to identify residues that play a key role in down-Regulation, Point mutations of residues within this region were examined for their ability to modulate receptor down-Regulation. The receptor with a mutation of Thr to Ala does not down-regulate, whereas the receptor with a mutation of Ser to Gly down-regulates with a time course similar to that of the wild type receptor. Taken together, these results suggest that the COOH-terminal tail is not essential for functional coupling but is necessary for down-Regulation and that Thr is critical for the agonist-mediated down-Regulation of the opiate receptor.
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Thr353, Located within the COOH-terminal Tail of the ´ Opiate Receptor, Is Involved in Receptor Down-Regulation
The Journal of biological chemistry, 1996Co-Authors: Svetlana Cvejic, Nino Trapaidze, Curt Cyr, Lakshmi A DeviAbstract:Abstract Prolonged exposure to abused drugs such as opiates causes decreased response to the drug; this reduced sensitivity is thought to be due to the loss of receptors, or down-Regulation. The molecular mechanism of the opiate receptor down-Regulation is not known. In order to address this, we generated a number of mutants of the opiate receptor COOH-terminal tail. When expressed in the Chinese hamster ovary cells, both the wild type and the receptor with a deletion of 37 COOH-terminal residues bind diprenorphine with comparable affinities and show similar decreases in cAMP levels in response to D-Ala2, D-Leu5, enkephalin (DADLE). However, the truncated receptor does not show down-Regulation from the cell surface upon prolonged exposure (2-48 h) to DADLE. In contrast, both the wild type receptor and the receptor with the deletion of only 15 COOH-terminal residues show substantial down-Regulation upon long term DADLE treatment. These results suggest that the region located between 15 and 37 residues from the COOH terminus is involved in the receptor down-Regulation. In order to identify residues that play a key role in down-Regulation, Point mutations of residues within this region were examined for their ability to modulate receptor down-Regulation. The receptor with a mutation of Thr to Ala does not down-regulate, whereas the receptor with a mutation of Ser to Gly down-regulates with a time course similar to that of the wild type receptor. Taken together, these results suggest that the COOH-terminal tail is not essential for functional coupling but is necessary for down-Regulation and that Thr is critical for the agonist-mediated down-Regulation of the opiate receptor.
J. Jimeno - One of the best experts on this subject based on the ideXlab platform.
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Unique features of the mode of action of ET-743
'Alphamed Press', 2002Co-Authors: M. D&apos, E. Erba, G. Damia, E. Galliera, L. Carrassa, S. Marchini, R. Mantovani, G. Tognon, R. Fruscio, J. JimenoAbstract:This paper describes the current knowledge of the primary mode of action of a natural product, ecteinascidin 743 (ET-743), derived from the marine tunicate Ecteinascidia turbinata. ET-743 was initially selected for preclinical development because of its potent antitumor activity observed against several human solid tumor types. In vitro, the drug is cytotoxic in the nanomolar range, and in the case of some very sensitive cell lines, in the picomolar range. The large potency differences observed among several solid tumor types indicate that this compound possesses some tumor selectivity, but the molecular basis of these differential effects remains to be elucidated. The present studies were undertaken to evaluate the mechanism of action of ET-743 in this context. The available information on ET-743 binding to DNA and its effects on transcriptional Regulation Point to a unique behavior of this drug, as it independently affects specific gene transcription in a promoter-dependent way. In addition, ET-743 shows a peculiar pattern of selectivity in cells with different defects in their DNA-repair pathways. These results highlight a unique property of ET-743, possibly explaining why it possesses antitumor activity against tumors that are refractory to standard anticancer drugs, all of which certainly act by mechanisms that are different from that of ET-743
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Unique features of the mode of action of ET-743.
The oncologist, 2002Co-Authors: Maurizio D'incalci, E. Erba, G. Damia, E. Galliera, L. Carrassa, S. Marchini, R. Mantovani, G. Tognon, R. Fruscio, J. JimenoAbstract:This paper describes the current knowledge of the primary mode of action of a natural product, ecteinascidin 743 (ET-743), derived from the marine tunicate Ecteinascidia turbinata. ET-743 was initially selected for preclinical development because of its potent antitumor activity observed against several human solid tumor types. In vitro, the drug is cytotoxic in the nanomolar range, and in the case of some very sensitive cell lines, in the picomolar range. The large potency differences observed among several solid tumor types indicate that this compound possesses some tumor selectivity, but the molecular basis of these differential effects remains to be elucidated. The present studies were undertaken to evaluate the mechanism of action of ET-743 in this context. The available information on ET-743 binding to DNA and its effects on transcriptional Regulation Point to a unique behavior of this drug, as it independently affects specific gene transcription in a promoter-dependent way. In addition, ET-743 shows a peculiar pattern of selectivity in cells with different defects in their DNA-repair pathways. These results highlight a unique property of ET-743, possibly explaining why it possesses antitumor activity against tumors that are refractory to standard anticancer drugs, all of which certainly act by mechanisms that are different from that of ET-743. The Oncologist 2002;7:210-216
