Archives of Pharmacal Research

  • 제28권11호
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  • Pages.1275-1281
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  • 2005
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  • 0253-6269(pISSN)
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  • 1976-3786(eISSN)
대한약학회 (The Pharmaceutical Society of Korea)
권호 표지

Direct Involvement of G Protein $\alpha_{q/11}$ Subunit in Regulation of Muscarinic Receptor-Mediated sAPP$\alpha$ Release

  • Kim Jin Hyoung (Division of Pharmaceutical Bioscience, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Kim Hwa-Jung (Research Institute of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University)
  • 발행 : 2005.11.01
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초록

The $G_{q/11}$ protein-coupled receptors, such as muscarinic (M1 & M3) receptors, have been shown to regulate the release of a soluble amyloid precursor protein (sAPP$\alpha$) produced from $\alpha$-secretase processing. However, there is no direct evidence for the precise characteristics of G proteins, and the signaling mechanism for the regulation of $G_{q/11}$ protein-coupled receptor mediated sAPP$\alpha$ release is not clearly understood. This study examined whether the muscarinic receptor-mediated release of sAPP$\alpha$ is directly regulated by $G\alpha_{q/11}$ proteins. The HEK293 cells were transiently cotransfected with muscarinic M3 receptors and a dominant-negative minigene construct of the G protein $\alpha$ subunit. The sAPP$\alpha$ release in the media was measured using an antibody specific for sAPP. The sAPP$\alpha$ release enhancement induced by muscarinic receptor stimulation was decreased by a $G_{q/11}$ minigene construct, whereas it was not blocked by a control minigene construct (the G$\alpha$ carboxy peptide in random order, G$\alpha_{q}$R) or $G\alpha_{j}$ constructs. This indicated a direct role of the $G\alpha_{q/11}$ protein in the regulation of muscarinic M3 receptor-mediated sAPP$\alpha$ release. We also investigated whether the transactivation of the epidermal growth factor receptor (EGFR) by a muscarinic agonist could regulate the sAPP$\alpha$ release in SH-SY5Y cells. Pretreatment of a specific EGFR kinase inhibitor, tyrophostin AG1478 (250 nM), blocked the EGF-stimulated sAPP$\alpha$ release, but did not block the oxoM­stimulated sAPP$\alpha$ release. This demonstrated that the transactivation of the EGFR by muscarinic receptor activation was not involved in the muscarinic receptor-mediated sAPP$\alpha$ release.

키워드

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