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GPCR dimerization in brainstem nuclei contributes to the development of hypertension
Author(s) -
Sun GwoChing,
Ho WenYu,
Chen BoRung,
Cheng PeiWen,
Cheng WenHan,
Hsu MeiChi,
Yeh TungChen,
Hsiao Michael,
Lu PeiJung,
Tseng ChingJiunn
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13074
Subject(s) - damgo , receptor , agonist , colocalization , medicine , endocrinology , chemistry , enkephalin , opioid receptor , biology , microbiology and biotechnology , opioid
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 α 2A ‐adrenoceptors. We hypothesized that α 2A ‐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/α 2A ‐adrenoceptor heterodimers was assessed with immunofluorescence and co‐immunoprecipitation methods, along with proximity ligation assays. Key Results Immunofluorescence staining revealed colocalization of α 2A ‐adrenoceptors and μ receptors in NTS neurons. Co‐immunoprecipitation revealed interactions between α 2A ‐adrenoceptors and μ receptors. In situ proximity ligation assays confirmed the presence of μ receptor/α 2A ‐adrenoceptor heterodimers in the NTS . Higher levels of endogenous endomorphin‐1 and μ receptor/α 2A ‐adrenoceptor heterodimers were found in the NTS of hypertensive rats, than in normotensive rats. Microinjection of the μ receptor agonist [ D ‐ A la 2 , M e P he 4 , G ly 5 ‐ol]‐enkephalin ( DAMGO ), but not that of the α 2A ‐adrenoceptor agonist guanfacine, into the NTS of normotensive rats increased μ receptor/α 2A ‐adrenoceptor heterodimer formation and BP elevation. The NO ‐dependent BP‐lowering effect of α 2A ‐adrenoceptor agonists was blunted following increased formation of μ receptor/α 2A ‐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/α 2A ‐adrenoceptor heterodimer formation and reduced the NO ‐dependent depressor effect of α 2A ‐adrenoceptor agonists. This process could contribute to the pathogenesis of hypertension.