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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/25/6/3395 |
| Summary: | 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. |
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| ISSN: | 1661-6596 1422-0067 |