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Muscarinic acetylcholine receptor-mediated phosphorylation of extracellular signal-regulated kinase in HSY salivary ductal cells involves distinct signaling pathways.
Yanuar, Rezon; Semba, Shingo; Nezu, Akihiro; Tanimura, Akihiko.
Afiliación
  • Yanuar R; Division of Pharmacology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan.
  • Semba S; Division of Pharmacology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan.
  • Nezu A; Division of Pharmacology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan.
  • Tanimura A; Division of Pharmacology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan. Electronic address: tanimura@hoku-iryo-u.ac.jp.
J Oral Biosci ; 66(2): 447-455, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38336259
ABSTRACT

OBJECTIVES:

Typical agonists of G protein-coupled receptors (GPCRs), including muscarinic acetylcholine receptors (mAChRs), activate both G-protein and ß-arrestin signaling systems, and are termed balanced agonists. In contrast, biased agonists selectively activate a single pathway, thereby offering therapeutic potential for the specific activation of that pathway. The mAChR agonists carbachol and pilocarpine are known to induce phosphorylation of extracellular signal-regulated kinase-1/2 (ERK1/2) via G-protein-dependent and -independent pathways, respectively. We investigated the involvement of ß-arrestin and its downstream mechanisms in the ERK1/2 phosphorylation induced by carbachol and pilocarpine in the human salivary ductal cell line, HSY cells.

METHODS:

HSY cells were stimulated with pilocarpine or carbachol, with or without various inhibitors. The cell lysates were analyzed by western blotting using the antibodies p44/p42MAPK and phosphor-p44/p42MAPK.

RESULTS:

Western blot analysis revealed that carbachol elicited greater stimulation of ERK1/2 phosphorylation compared to pilocarpine. ERK1/2 phosphorylation was inhibited by atropine and gefitinib, suggesting that mAChR activation induces transactivation of epidermal growth factor receptors (EGFR). Moreover, inhibition of carbachol-mediated ERK1/2 phosphorylation was achieved by GF-109203X (a PKC inhibitor), a ßARK1/GRK2 inhibitor, barbadin (a ß-arrestin inhibitor), pitstop 2 (a clathrin inhibitor), and dynole 34-2 (a dynamin inhibitor). In contrast, pilocarpine-mediated ERK1/2 phosphorylation was only inhibited by barbadin (a ß-arrestin inhibitor) and PP2 (a Src inhibitor).

CONCLUSION:

Carbachol activates both G-protein and ß-arrestin pathways, whereas pilocarpine exclusively activates the ß-arrestin pathway. Additionally, downstream of ß-arrestin, carbachol activates clathrin-dependent internalization, while pilocarpine activates Src.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pilocarpina / Carbacol / Transducción de Señal / Receptores Muscarínicos / Agonistas Muscarínicos Límite: Humans Idioma: En Revista: J Oral Biosci Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Países Bajos
Texto completo
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Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pilocarpina / Carbacol / Transducción de Señal / Receptores Muscarínicos / Agonistas Muscarínicos Límite: Humans Idioma: En Revista: J Oral Biosci Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Países Bajos