The Experts below are selected from a list of 74148 Experts worldwide ranked by ideXlab platform
Darrell A Jackson - One of the best experts on this subject based on the ideXlab platform.
-
differential role of beta arrestin Ubiquitination in agonist promoted down regulation of m 1 vs m 2 muscarinic acetylcholine receptors
Journal of Molecular Signaling, 2008Co-Authors: Valerie A Mosser, Kymry T Jones, Katie M Hoffman, Nael A Mccarty, Darrell A JacksonAbstract:Sustained agonist-promoted Ubiquitination of β-arrestin has been correlated with increased stability of the GPCR – β-arrestin complex. Moreover, abrogation of β-arrestin Ubiquitination has been reported to inhibit receptor internalization with minimal effects on receptor degradation. Herein we report that agonist activation of M1 mAChRs produces a sustained β-arrestin Ubiquitination but no stable co-localization with β-arrestin. In contrast, sustained Ubiquitination of β-arrestin by activation of M2 mAChRs does result in stable co-localization between the M2 mAChR and β-arrestin. Internalization of receptors was unaffected by proteasome inhibitors, but down-regulation was significantly reduced, suggesting a role for the Ubiquitination machinery in promoting down-regulation of the receptors. Given the Ubiquitination status of β-arrestin following agonist treatment, we sought to determine the effects of β-arrestin Ubiquitination on M1 and M2 mAChR down-regulation. A constitutively ubiquitinated β-arrestin 2 chimera in which ubiquitin is fused to the C-terminus of β-arrestin 2 (YFP-β-arrestin 2-Ub) significantly increased agonist-promoted down-regulation of both M1 and M2 mAChRs, with the effect substantially higher on the M2 mAChR. Based on this observation, we were interested in examining the effects of disruption of potential Ubiquitination sites in the β-arrestin sequence on receptor down-regulation. Agonist-promoted internalization of the M2 mAChR was not affected by expression of β-arrestin lysine mutants lacking putative Ubiquitination sites, β-arrestin 2K18R, K107R, K108R, K207R, K296R, while down-regulation and stable co-localiztion of the receptor with this β-arrestin lysine mutant were significantly reduced. Interestingly, expression of β-arrestin 2K18R, K107R, K108R, K207R, K296R increased the agonist-promoted down-regulation of the M1 mAChR but did not result in a stable co-localiztion of the receptor with this β-arrestin lysine mutant. These findings indicate that Ubiquitination of β-arrestin has a distinct role in the differential trafficking and degradation of M1 and M2 mAChRs.
-
Differential role of beta-arrestin Ubiquitination in agonist-promoted down-regulation of M_1 vs M_2 muscarinic acetylcholine receptors
Journal of Molecular Signaling, 2008Co-Authors: Valerie A Mosser, Kymry T Jones, Katie M Hoffman, Nael A Mccarty, Darrell A JacksonAbstract:Background Sustained agonist-promoted Ubiquitination of β-arrestin has been correlated with increased stability of the GPCR – β-arrestin complex. Moreover, abrogation of β-arrestin Ubiquitination has been reported to inhibit receptor internalization with minimal effects on receptor degradation. Results Herein we report that agonist activation of M_1 mAChRs produces a sustained β-arrestin Ubiquitination but no stable co-localization with β-arrestin. In contrast, sustained Ubiquitination of β-arrestin by activation of M_2 mAChRs does result in stable co-localization between the M_2 mAChR and β-arrestin. Internalization of receptors was unaffected by proteasome inhibitors, but down-regulation was significantly reduced, suggesting a role for the Ubiquitination machinery in promoting down-regulation of the receptors. Given the Ubiquitination status of β-arrestin following agonist treatment, we sought to determine the effects of β-arrestin Ubiquitination on M_1 and M_2 mAChR down-regulation. A constitutively ubiquitinated β-arrestin 2 chimera in which ubiquitin is fused to the C-terminus of β-arrestin 2 (YFP-β-arrestin 2-Ub) significantly increased agonist-promoted down-regulation of both M_1 and M_2 mAChRs, with the effect substantially higher on the M_2 mAChR. Based on this observation, we were interested in examining the effects of disruption of potential Ubiquitination sites in the β-arrestin sequence on receptor down-regulation. Agonist-promoted internalization of the M_2 mAChR was not affected by expression of β-arrestin lysine mutants lacking putative Ubiquitination sites, β-arrestin 2^K18R, K107R, K108R, K207R, K296R, while down-regulation and stable co-localiztion of the receptor with this β-arrestin lysine mutant were significantly reduced. Interestingly, expression of β-arrestin 2^K18R, K107R, K108R, K207R, K296R increased the agonist-promoted down-regulation of the M_1 mAChR but did not result in a stable co-localiztion of the receptor with this β-arrestin lysine mutant. Conclusion These findings indicate that Ubiquitination of β-arrestin has a distinct role in the differential trafficking and degradation of M_1 and M_2 mAChRs.
Dietmar Benke - One of the best experts on this subject based on the ideXlab platform.
-
lys 63 linked Ubiquitination of γ aminobutyric acid gaba type b1 at multiple sites by the e3 ligase mind bomb 2 targets gabab receptors to lysosomal degradation
Journal of Biological Chemistry, 2016Co-Authors: Khaled Zemoura, Claudia Trumpler, Dietmar BenkeAbstract:GABAB receptors are heterodimeric G protein-coupled receptors, which control neuronal excitability by mediating prolonged inhibition. The magnitude of GABAB receptor-mediated inhibition essentially depends on the amount of receptors in the plasma membrane. However, the factors regulating cell surface expression of GABAB receptors are poorly characterized. Cell surface GABAB receptors are constitutively internalized and either recycled to the plasma membrane or degraded in lysosomes. The signal that sorts GABAB receptors to lysosomes is currently unknown. Here we show that Mind bomb-2 (MIB2)-mediated Lys-63-linked Ubiquitination of the GABAB1 subunit at multiple sites is the lysosomal sorting signal for GABAB receptors. We found that inhibition of lysosomal activity in cultured rat cortical neurons increased the fraction of Lys-63-linked ubiquitinated GABAB receptors and enhanced the expression of total as well as cell surface GABAB receptors. Mutational inactivation of four putative Ubiquitination sites in the GABAB1 subunit significantly diminished Lys-63-linked Ubiquitination of GABAB receptors and prevented their lysosomal degradation. We identified MIB2 as the E3 ligase triggering Lys-63-linked Ubiquitination and lysosomal degradation of GABAB receptors. Finally, we show that sustained activation of glutamate receptors, a condition occurring in brain ischemia that down-regulates GABAB receptors, considerably increased the expression of MIB2 and Lys-63-linked Ubiquitination of GABAB receptors. Interfering with Lys-63-linked Ubiquitination by overexpressing ubiquitin mutants or GABAB1 mutants deficient in Lys-63-linked Ubiquitination prevented glutamate-induced down-regulation of the receptors. These findings indicate that Lys-63-linked Ubiquitination of GABAB1 at multiple sites by MIB2 controls sorting of GABAB receptors to lysosomes for degradation under physiological and pathological conditions.
Valerie A Mosser - One of the best experts on this subject based on the ideXlab platform.
-
differential role of beta arrestin Ubiquitination in agonist promoted down regulation of m 1 vs m 2 muscarinic acetylcholine receptors
Journal of Molecular Signaling, 2008Co-Authors: Valerie A Mosser, Kymry T Jones, Katie M Hoffman, Nael A Mccarty, Darrell A JacksonAbstract:Sustained agonist-promoted Ubiquitination of β-arrestin has been correlated with increased stability of the GPCR – β-arrestin complex. Moreover, abrogation of β-arrestin Ubiquitination has been reported to inhibit receptor internalization with minimal effects on receptor degradation. Herein we report that agonist activation of M1 mAChRs produces a sustained β-arrestin Ubiquitination but no stable co-localization with β-arrestin. In contrast, sustained Ubiquitination of β-arrestin by activation of M2 mAChRs does result in stable co-localization between the M2 mAChR and β-arrestin. Internalization of receptors was unaffected by proteasome inhibitors, but down-regulation was significantly reduced, suggesting a role for the Ubiquitination machinery in promoting down-regulation of the receptors. Given the Ubiquitination status of β-arrestin following agonist treatment, we sought to determine the effects of β-arrestin Ubiquitination on M1 and M2 mAChR down-regulation. A constitutively ubiquitinated β-arrestin 2 chimera in which ubiquitin is fused to the C-terminus of β-arrestin 2 (YFP-β-arrestin 2-Ub) significantly increased agonist-promoted down-regulation of both M1 and M2 mAChRs, with the effect substantially higher on the M2 mAChR. Based on this observation, we were interested in examining the effects of disruption of potential Ubiquitination sites in the β-arrestin sequence on receptor down-regulation. Agonist-promoted internalization of the M2 mAChR was not affected by expression of β-arrestin lysine mutants lacking putative Ubiquitination sites, β-arrestin 2K18R, K107R, K108R, K207R, K296R, while down-regulation and stable co-localiztion of the receptor with this β-arrestin lysine mutant were significantly reduced. Interestingly, expression of β-arrestin 2K18R, K107R, K108R, K207R, K296R increased the agonist-promoted down-regulation of the M1 mAChR but did not result in a stable co-localiztion of the receptor with this β-arrestin lysine mutant. These findings indicate that Ubiquitination of β-arrestin has a distinct role in the differential trafficking and degradation of M1 and M2 mAChRs.
-
Differential role of beta-arrestin Ubiquitination in agonist-promoted down-regulation of M_1 vs M_2 muscarinic acetylcholine receptors
Journal of Molecular Signaling, 2008Co-Authors: Valerie A Mosser, Kymry T Jones, Katie M Hoffman, Nael A Mccarty, Darrell A JacksonAbstract:Background Sustained agonist-promoted Ubiquitination of β-arrestin has been correlated with increased stability of the GPCR – β-arrestin complex. Moreover, abrogation of β-arrestin Ubiquitination has been reported to inhibit receptor internalization with minimal effects on receptor degradation. Results Herein we report that agonist activation of M_1 mAChRs produces a sustained β-arrestin Ubiquitination but no stable co-localization with β-arrestin. In contrast, sustained Ubiquitination of β-arrestin by activation of M_2 mAChRs does result in stable co-localization between the M_2 mAChR and β-arrestin. Internalization of receptors was unaffected by proteasome inhibitors, but down-regulation was significantly reduced, suggesting a role for the Ubiquitination machinery in promoting down-regulation of the receptors. Given the Ubiquitination status of β-arrestin following agonist treatment, we sought to determine the effects of β-arrestin Ubiquitination on M_1 and M_2 mAChR down-regulation. A constitutively ubiquitinated β-arrestin 2 chimera in which ubiquitin is fused to the C-terminus of β-arrestin 2 (YFP-β-arrestin 2-Ub) significantly increased agonist-promoted down-regulation of both M_1 and M_2 mAChRs, with the effect substantially higher on the M_2 mAChR. Based on this observation, we were interested in examining the effects of disruption of potential Ubiquitination sites in the β-arrestin sequence on receptor down-regulation. Agonist-promoted internalization of the M_2 mAChR was not affected by expression of β-arrestin lysine mutants lacking putative Ubiquitination sites, β-arrestin 2^K18R, K107R, K108R, K207R, K296R, while down-regulation and stable co-localiztion of the receptor with this β-arrestin lysine mutant were significantly reduced. Interestingly, expression of β-arrestin 2^K18R, K107R, K108R, K207R, K296R increased the agonist-promoted down-regulation of the M_1 mAChR but did not result in a stable co-localiztion of the receptor with this β-arrestin lysine mutant. Conclusion These findings indicate that Ubiquitination of β-arrestin has a distinct role in the differential trafficking and degradation of M_1 and M_2 mAChRs.
Khaled Zemoura - One of the best experts on this subject based on the ideXlab platform.
-
lys 63 linked Ubiquitination of γ aminobutyric acid gaba type b1 at multiple sites by the e3 ligase mind bomb 2 targets gabab receptors to lysosomal degradation
Journal of Biological Chemistry, 2016Co-Authors: Khaled Zemoura, Claudia Trumpler, Dietmar BenkeAbstract:GABAB receptors are heterodimeric G protein-coupled receptors, which control neuronal excitability by mediating prolonged inhibition. The magnitude of GABAB receptor-mediated inhibition essentially depends on the amount of receptors in the plasma membrane. However, the factors regulating cell surface expression of GABAB receptors are poorly characterized. Cell surface GABAB receptors are constitutively internalized and either recycled to the plasma membrane or degraded in lysosomes. The signal that sorts GABAB receptors to lysosomes is currently unknown. Here we show that Mind bomb-2 (MIB2)-mediated Lys-63-linked Ubiquitination of the GABAB1 subunit at multiple sites is the lysosomal sorting signal for GABAB receptors. We found that inhibition of lysosomal activity in cultured rat cortical neurons increased the fraction of Lys-63-linked ubiquitinated GABAB receptors and enhanced the expression of total as well as cell surface GABAB receptors. Mutational inactivation of four putative Ubiquitination sites in the GABAB1 subunit significantly diminished Lys-63-linked Ubiquitination of GABAB receptors and prevented their lysosomal degradation. We identified MIB2 as the E3 ligase triggering Lys-63-linked Ubiquitination and lysosomal degradation of GABAB receptors. Finally, we show that sustained activation of glutamate receptors, a condition occurring in brain ischemia that down-regulates GABAB receptors, considerably increased the expression of MIB2 and Lys-63-linked Ubiquitination of GABAB receptors. Interfering with Lys-63-linked Ubiquitination by overexpressing ubiquitin mutants or GABAB1 mutants deficient in Lys-63-linked Ubiquitination prevented glutamate-induced down-regulation of the receptors. These findings indicate that Lys-63-linked Ubiquitination of GABAB1 at multiple sites by MIB2 controls sorting of GABAB receptors to lysosomes for degradation under physiological and pathological conditions.
Katie M Hoffman - One of the best experts on this subject based on the ideXlab platform.
-
differential role of beta arrestin Ubiquitination in agonist promoted down regulation of m 1 vs m 2 muscarinic acetylcholine receptors
Journal of Molecular Signaling, 2008Co-Authors: Valerie A Mosser, Kymry T Jones, Katie M Hoffman, Nael A Mccarty, Darrell A JacksonAbstract:Sustained agonist-promoted Ubiquitination of β-arrestin has been correlated with increased stability of the GPCR – β-arrestin complex. Moreover, abrogation of β-arrestin Ubiquitination has been reported to inhibit receptor internalization with minimal effects on receptor degradation. Herein we report that agonist activation of M1 mAChRs produces a sustained β-arrestin Ubiquitination but no stable co-localization with β-arrestin. In contrast, sustained Ubiquitination of β-arrestin by activation of M2 mAChRs does result in stable co-localization between the M2 mAChR and β-arrestin. Internalization of receptors was unaffected by proteasome inhibitors, but down-regulation was significantly reduced, suggesting a role for the Ubiquitination machinery in promoting down-regulation of the receptors. Given the Ubiquitination status of β-arrestin following agonist treatment, we sought to determine the effects of β-arrestin Ubiquitination on M1 and M2 mAChR down-regulation. A constitutively ubiquitinated β-arrestin 2 chimera in which ubiquitin is fused to the C-terminus of β-arrestin 2 (YFP-β-arrestin 2-Ub) significantly increased agonist-promoted down-regulation of both M1 and M2 mAChRs, with the effect substantially higher on the M2 mAChR. Based on this observation, we were interested in examining the effects of disruption of potential Ubiquitination sites in the β-arrestin sequence on receptor down-regulation. Agonist-promoted internalization of the M2 mAChR was not affected by expression of β-arrestin lysine mutants lacking putative Ubiquitination sites, β-arrestin 2K18R, K107R, K108R, K207R, K296R, while down-regulation and stable co-localiztion of the receptor with this β-arrestin lysine mutant were significantly reduced. Interestingly, expression of β-arrestin 2K18R, K107R, K108R, K207R, K296R increased the agonist-promoted down-regulation of the M1 mAChR but did not result in a stable co-localiztion of the receptor with this β-arrestin lysine mutant. These findings indicate that Ubiquitination of β-arrestin has a distinct role in the differential trafficking and degradation of M1 and M2 mAChRs.
-
Differential role of beta-arrestin Ubiquitination in agonist-promoted down-regulation of M_1 vs M_2 muscarinic acetylcholine receptors
Journal of Molecular Signaling, 2008Co-Authors: Valerie A Mosser, Kymry T Jones, Katie M Hoffman, Nael A Mccarty, Darrell A JacksonAbstract:Background Sustained agonist-promoted Ubiquitination of β-arrestin has been correlated with increased stability of the GPCR – β-arrestin complex. Moreover, abrogation of β-arrestin Ubiquitination has been reported to inhibit receptor internalization with minimal effects on receptor degradation. Results Herein we report that agonist activation of M_1 mAChRs produces a sustained β-arrestin Ubiquitination but no stable co-localization with β-arrestin. In contrast, sustained Ubiquitination of β-arrestin by activation of M_2 mAChRs does result in stable co-localization between the M_2 mAChR and β-arrestin. Internalization of receptors was unaffected by proteasome inhibitors, but down-regulation was significantly reduced, suggesting a role for the Ubiquitination machinery in promoting down-regulation of the receptors. Given the Ubiquitination status of β-arrestin following agonist treatment, we sought to determine the effects of β-arrestin Ubiquitination on M_1 and M_2 mAChR down-regulation. A constitutively ubiquitinated β-arrestin 2 chimera in which ubiquitin is fused to the C-terminus of β-arrestin 2 (YFP-β-arrestin 2-Ub) significantly increased agonist-promoted down-regulation of both M_1 and M_2 mAChRs, with the effect substantially higher on the M_2 mAChR. Based on this observation, we were interested in examining the effects of disruption of potential Ubiquitination sites in the β-arrestin sequence on receptor down-regulation. Agonist-promoted internalization of the M_2 mAChR was not affected by expression of β-arrestin lysine mutants lacking putative Ubiquitination sites, β-arrestin 2^K18R, K107R, K108R, K207R, K296R, while down-regulation and stable co-localiztion of the receptor with this β-arrestin lysine mutant were significantly reduced. Interestingly, expression of β-arrestin 2^K18R, K107R, K108R, K207R, K296R increased the agonist-promoted down-regulation of the M_1 mAChR but did not result in a stable co-localiztion of the receptor with this β-arrestin lysine mutant. Conclusion These findings indicate that Ubiquitination of β-arrestin has a distinct role in the differential trafficking and degradation of M_1 and M_2 mAChRs.
