GPCR dimerization in brainstem nuclei contributes to the development of hypertension

Gwo Ching Sun, Wen Yu Ho, Bo Rung Chen, Pei Wen Cheng, Wen Han Cheng, Mei Chi Hsu, Tung Chen Yeh, Michael Hsiao, Pei Jung Lu, Ching Jiunn Tseng

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Abstract

Background and Purpose μ-Opioid receptors, pro-opiomelanocortin and pro-enkephalin are highly expressed in the nucleus tractus solitarii (NTS) and μ receptor agonists given to the NTS dose-dependently increased BP. However, the molecular mechanisms of this process remain unclear. In vitro, μ receptors heterodimerize with α2A-adrenoceptors. We hypothesized that α2A-adrenoceptor agonists would lose their depressor effects when their receptors heterodimerize in the NTS with μ receptors. Experimental Approach We microinjected μ-opioid agonists and antagonists into the NTS of rats and measured changes in BP. Formation of μ receptor/α2A-adrenoceptor heterodimers was assessed with immunofluorescence and co-immunoprecipitation methods, along with proximity ligation assays. Key Results Immunofluorescence staining revealed colocalization of α2A-adrenoceptors and μ receptors in NTS neurons. Co-immunoprecipitation revealed interactions between α2A-adrenoceptors and μ receptors. In situ proximity ligation assays confirmed the presence of μ receptor/α2A-adrenoceptor heterodimers in the NTS. Higher levels of endogenous endomorphin-1 and μ receptor/α2A-adrenoceptor heterodimers were found in the NTS of hypertensive rats, than in normotensive rats. Microinjection of the μ receptor agonist [D-Ala2, MePhe4, Gly5-ol]-enkephalin (DAMGO), but not that of the α2A-adrenoceptor agonist guanfacine, into the NTS of normotensive rats increased μ receptor/α2A-adrenoceptor heterodimer formation and BP elevation. The NO-dependent BP-lowering effect of α2A-adrenoceptor agonists was blunted following increased formation of μ receptor/α2A-adrenoceptor heterodimers in the NTS of hypertensive rats and DAMGO-treated normotensive rats. Conclusions and Implications Increases in endogenous μ receptor agonists in the NTS induced μ receptor/α2A-adrenoceptor heterodimer formation and reduced the NO-dependent depressor effect of α2A-adrenoceptor agonists. This process could contribute to the pathogenesis of hypertension.

Original languageEnglish
Pages (from-to)2507-2518
Number of pages12
JournalBritish Journal of Pharmacology
Volume172
Issue number10
DOIs
Publication statusPublished - 2015 May 1

All Science Journal Classification (ASJC) codes

  • Pharmacology

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    Sun, G. C., Ho, W. Y., Chen, B. R., Cheng, P. W., Cheng, W. H., Hsu, M. C., Yeh, T. C., Hsiao, M., Lu, P. J., & Tseng, C. J. (2015). GPCR dimerization in brainstem nuclei contributes to the development of hypertension. British Journal of Pharmacology, 172(10), 2507-2518. https://doi.org/10.1111/bph.13074