Sequestration of Gβγ by deubiquitinated arrestins into the nucleus as a novel desensitization mechanism of G protein–coupled receptors
Abstract Background Desensitization of G protein–coupled receptors (GPCRs) refers to a rapid attenuation of responsiveness that occurs with repeated or continuous exposure to agonists. GRK-mediated phosphorylation and subsequent binding with arrestins in the activated receptor cytoplasmic cavity in...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-022-01013-z |
| _version_ | 1811177011977125888 |
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| author | Xiao Min Ningning Sun Shujie Wang Xiaohan Zhang Kyeong-Man Kim |
| author_facet | Xiao Min Ningning Sun Shujie Wang Xiaohan Zhang Kyeong-Man Kim |
| author_sort | Xiao Min |
| collection | DOAJ |
| description | Abstract Background Desensitization of G protein–coupled receptors (GPCRs) refers to a rapid attenuation of responsiveness that occurs with repeated or continuous exposure to agonists. GRK-mediated phosphorylation and subsequent binding with arrestins in the activated receptor cytoplasmic cavity in competition with G proteins has been suggested as the conventional mechanism of desensitization. Along with widely accepted conventional mechanism of desensitization, studies of various GPCRs including dopamine D2-like receptors (D2R, D3R, D4R) have suggested the existence of another desensitization mechanism. In this study, loss-of-function approaches and D2-like receptor mutants that display different desensitization properties were used to elucidate the molecular mechanisms responsible for desensitization. Results Desensitization development entailed the signaling cascade composed of Src, PDK1, and Akt, the latter of which in turn interacted with USP33, an arrestin deubiquitinase, to promote arrestin deubiquitination. The deubiquitinated arrestin subsequently formed a complex with Gβγ and translocated to the nucleus via an importin complex, wherein it sequestered Gβγ from the receptor and Gα, thereby attenuating receptor signaling. As in D2-like receptors, both USP33 and importin β1 were involved in the desensitization of the β2 adrenoceptor. Conclusions In addition to the conventional mechanism of desensitization, which occurs on the plasma membrane and in the cytosol, this study provides a new insight that another desensitization pathway in which nuclear trafficking plays a critical role is operating. It is plausible that multiple, complementary desensitization measures are in place to properly induce desensitization depending on receptor characteristics or the surrounding environment. Video Abstract |
| first_indexed | 2024-04-10T21:01:03Z |
| format | Article |
| id | doaj.art-821709d2f9954b0ab3725ffa08df6c5d |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-04-10T21:01:03Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-821709d2f9954b0ab3725ffa08df6c5d2023-01-22T12:20:06ZengBMCCell Communication and Signaling1478-811X2023-01-0121112010.1186/s12964-022-01013-zSequestration of Gβγ by deubiquitinated arrestins into the nucleus as a novel desensitization mechanism of G protein–coupled receptorsXiao Min0Ningning Sun1Shujie Wang2Xiaohan Zhang3Kyeong-Man Kim4Department of Pharmacology, College of Pharmacy, Chonnam National UniversityDepartment of Pharmacology, College of Pharmacy, Chonnam National UniversityDepartment of Pharmacology, College of Pharmacy, Chonnam National UniversityDepartment of Pharmacology, College of Pharmacy, Chonnam National UniversityDepartment of Pharmacology, College of Pharmacy, Chonnam National UniversityAbstract Background Desensitization of G protein–coupled receptors (GPCRs) refers to a rapid attenuation of responsiveness that occurs with repeated or continuous exposure to agonists. GRK-mediated phosphorylation and subsequent binding with arrestins in the activated receptor cytoplasmic cavity in competition with G proteins has been suggested as the conventional mechanism of desensitization. Along with widely accepted conventional mechanism of desensitization, studies of various GPCRs including dopamine D2-like receptors (D2R, D3R, D4R) have suggested the existence of another desensitization mechanism. In this study, loss-of-function approaches and D2-like receptor mutants that display different desensitization properties were used to elucidate the molecular mechanisms responsible for desensitization. Results Desensitization development entailed the signaling cascade composed of Src, PDK1, and Akt, the latter of which in turn interacted with USP33, an arrestin deubiquitinase, to promote arrestin deubiquitination. The deubiquitinated arrestin subsequently formed a complex with Gβγ and translocated to the nucleus via an importin complex, wherein it sequestered Gβγ from the receptor and Gα, thereby attenuating receptor signaling. As in D2-like receptors, both USP33 and importin β1 were involved in the desensitization of the β2 adrenoceptor. Conclusions In addition to the conventional mechanism of desensitization, which occurs on the plasma membrane and in the cytosol, this study provides a new insight that another desensitization pathway in which nuclear trafficking plays a critical role is operating. It is plausible that multiple, complementary desensitization measures are in place to properly induce desensitization depending on receptor characteristics or the surrounding environment. Video Abstracthttps://doi.org/10.1186/s12964-022-01013-zDopamine D2-like receptorβ2 adrenoceptorDesensitizationSrcUSP33Nuclear trafficking |
| spellingShingle | Xiao Min Ningning Sun Shujie Wang Xiaohan Zhang Kyeong-Man Kim Sequestration of Gβγ by deubiquitinated arrestins into the nucleus as a novel desensitization mechanism of G protein–coupled receptors Cell Communication and Signaling Dopamine D2-like receptor β2 adrenoceptor Desensitization Src USP33 Nuclear trafficking |
| title | Sequestration of Gβγ by deubiquitinated arrestins into the nucleus as a novel desensitization mechanism of G protein–coupled receptors |
| title_full | Sequestration of Gβγ by deubiquitinated arrestins into the nucleus as a novel desensitization mechanism of G protein–coupled receptors |
| title_fullStr | Sequestration of Gβγ by deubiquitinated arrestins into the nucleus as a novel desensitization mechanism of G protein–coupled receptors |
| title_full_unstemmed | Sequestration of Gβγ by deubiquitinated arrestins into the nucleus as a novel desensitization mechanism of G protein–coupled receptors |
| title_short | Sequestration of Gβγ by deubiquitinated arrestins into the nucleus as a novel desensitization mechanism of G protein–coupled receptors |
| title_sort | sequestration of gβγ by deubiquitinated arrestins into the nucleus as a novel desensitization mechanism of g protein coupled receptors |
| topic | Dopamine D2-like receptor β2 adrenoceptor Desensitization Src USP33 Nuclear trafficking |
| url | https://doi.org/10.1186/s12964-022-01013-z |
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