Histamine H<sub>1</sub> Receptor-Mediated JNK Phosphorylation Is Regulated by G<sub>q</sub> Protein-Dependent but Arrestin-Independent Pathways
Arrestins are known to be involved not only in the desensitization and internalization of G protein-coupled receptors but also in the G protein-independent activation of mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), to...
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/6/3395 |
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| author | Shotaro Michinaga Ayaka Nagata Ryosuke Ogami Yasuhiro Ogawa Shigeru Hishinuma |
| author_facet | Shotaro Michinaga Ayaka Nagata Ryosuke Ogami Yasuhiro Ogawa Shigeru Hishinuma |
| author_sort | Shotaro Michinaga |
| collection | DOAJ |
| description | Arrestins are known to be involved not only in the desensitization and internalization of G protein-coupled receptors but also in the G protein-independent activation of mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), to regulate cell proliferation and inflammation. Our previous study revealed that the histamine H<sub>1</sub> receptor-mediated activation of ERK is dually regulated by G<sub>q</sub> proteins and arrestins. In this study, we investigated the roles of G<sub>q</sub> proteins and arrestins in the H<sub>1</sub> receptor-mediated activation of JNK in Chinese hamster ovary (CHO) cells expressing wild-type (WT) human H<sub>1</sub> receptors, the G<sub>q</sub> protein-biased mutant S487TR, and the arrestin-biased mutant S487A. In these mutants, the Ser487 residue in the C-terminus region of the WT was truncated (S487TR) or mutated to alanine (S487A). Histamine significantly stimulated JNK phosphorylation in CHO cells expressing WT and S487TR but not S487A. Histamine-induced JNK phosphorylation in CHO cells expressing WT and S487TR was suppressed by inhibitors against H<sub>1</sub> receptors (ketotifen and diphenhydramine), G<sub>q</sub> proteins (YM-254890), and protein kinase C (PKC) (GF109203X) as well as an intracellular Ca<sup>2+</sup> chelator (BAPTA-AM) but not by inhibitors against G protein-coupled receptor kinases (GRK2/3) (cmpd101), β-arrestin2 (β-arrestin2 siRNA), and clathrin (hypertonic sucrose). These results suggest that the H<sub>1</sub> receptor-mediated phosphorylation of JNK is regulated by G<sub>q</sub>-protein/Ca<sup>2+</sup>/PKC-dependent but GRK/arrestin/clathrin-independent pathways. |
| first_indexed | 2024-04-24T18:11:57Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T18:11:57Z |
| publishDate | 2024-03-01 |
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| spelling | doaj.art-fac5ea2426944d08bf986590504225bd2024-03-27T13:45:58ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01256339510.3390/ijms25063395Histamine H<sub>1</sub> Receptor-Mediated JNK Phosphorylation Is Regulated by G<sub>q</sub> Protein-Dependent but Arrestin-Independent PathwaysShotaro Michinaga0Ayaka Nagata1Ryosuke Ogami2Yasuhiro Ogawa3Shigeru Hishinuma4Department of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, JapanDepartment of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, JapanDepartment of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, JapanDepartment of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, JapanDepartment of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, JapanArrestins are known to be involved not only in the desensitization and internalization of G protein-coupled receptors but also in the G protein-independent activation of mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), to regulate cell proliferation and inflammation. Our previous study revealed that the histamine H<sub>1</sub> receptor-mediated activation of ERK is dually regulated by G<sub>q</sub> proteins and arrestins. In this study, we investigated the roles of G<sub>q</sub> proteins and arrestins in the H<sub>1</sub> receptor-mediated activation of JNK in Chinese hamster ovary (CHO) cells expressing wild-type (WT) human H<sub>1</sub> receptors, the G<sub>q</sub> protein-biased mutant S487TR, and the arrestin-biased mutant S487A. In these mutants, the Ser487 residue in the C-terminus region of the WT was truncated (S487TR) or mutated to alanine (S487A). Histamine significantly stimulated JNK phosphorylation in CHO cells expressing WT and S487TR but not S487A. Histamine-induced JNK phosphorylation in CHO cells expressing WT and S487TR was suppressed by inhibitors against H<sub>1</sub> receptors (ketotifen and diphenhydramine), G<sub>q</sub> proteins (YM-254890), and protein kinase C (PKC) (GF109203X) as well as an intracellular Ca<sup>2+</sup> chelator (BAPTA-AM) but not by inhibitors against G protein-coupled receptor kinases (GRK2/3) (cmpd101), β-arrestin2 (β-arrestin2 siRNA), and clathrin (hypertonic sucrose). These results suggest that the H<sub>1</sub> receptor-mediated phosphorylation of JNK is regulated by G<sub>q</sub>-protein/Ca<sup>2+</sup>/PKC-dependent but GRK/arrestin/clathrin-independent pathways.https://www.mdpi.com/1422-0067/25/6/3395β-arrestin2c-Jun N-terminal kinaseG<sub>q</sub> proteinhistamine H<sub>1</sub> receptormitogen-activated protein kinaseprotein kinase C |
| spellingShingle | Shotaro Michinaga Ayaka Nagata Ryosuke Ogami Yasuhiro Ogawa Shigeru Hishinuma Histamine H<sub>1</sub> Receptor-Mediated JNK Phosphorylation Is Regulated by G<sub>q</sub> Protein-Dependent but Arrestin-Independent Pathways International Journal of Molecular Sciences β-arrestin2 c-Jun N-terminal kinase G<sub>q</sub> protein histamine H<sub>1</sub> receptor mitogen-activated protein kinase protein kinase C |
| title | Histamine H<sub>1</sub> Receptor-Mediated JNK Phosphorylation Is Regulated by G<sub>q</sub> Protein-Dependent but Arrestin-Independent Pathways |
| title_full | Histamine H<sub>1</sub> Receptor-Mediated JNK Phosphorylation Is Regulated by G<sub>q</sub> Protein-Dependent but Arrestin-Independent Pathways |
| title_fullStr | Histamine H<sub>1</sub> Receptor-Mediated JNK Phosphorylation Is Regulated by G<sub>q</sub> Protein-Dependent but Arrestin-Independent Pathways |
| title_full_unstemmed | Histamine H<sub>1</sub> Receptor-Mediated JNK Phosphorylation Is Regulated by G<sub>q</sub> Protein-Dependent but Arrestin-Independent Pathways |
| title_short | Histamine H<sub>1</sub> Receptor-Mediated JNK Phosphorylation Is Regulated by G<sub>q</sub> Protein-Dependent but Arrestin-Independent Pathways |
| title_sort | histamine h sub 1 sub receptor mediated jnk phosphorylation is regulated by g sub q sub protein dependent but arrestin independent pathways |
| topic | β-arrestin2 c-Jun N-terminal kinase G<sub>q</sub> protein histamine H<sub>1</sub> receptor mitogen-activated protein kinase protein kinase C |
| url | https://www.mdpi.com/1422-0067/25/6/3395 |
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