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GPCR dimerization in brainstem nuclei contributes to the development of hypertension.

ABSTRACT: ?-Opioid receptors, pro-opiomelanocortin and pro-enkephalin are highly expressed in the nucleus tractus solitarii (NTS) and ? receptor agonists given to the NTS dose-dependently increased BP. However, the molecular mechanisms of this process remain unclear. In vitro, ? receptors heterodimerize with ?2A -adrenoceptors. We hypothesized that ?2A -adrenoceptor agonists would lose their depressor effects when their receptors heterodimerize in the NTS with ? receptors.We microinjected ?-opioid agonists and antagonists into the NTS of rats and measured changes in BP. Formation of ? receptor/?2A -adrenoceptor heterodimers was assessed with immunofluorescence and co-immunoprecipitation methods, along with proximity ligation assays.Immunofluorescence staining revealed colocalization of ?2A -adrenoceptors and ? receptors in NTS neurons. Co-immunoprecipitation revealed interactions between ?2A -adrenoceptors and ? receptors. In situ proximity ligation assays confirmed the presence of ? receptor/?2A -adrenoceptor heterodimers in the NTS. Higher levels of endogenous endomorphin-1 and ? receptor/?2A -adrenoceptor heterodimers were found in the NTS of hypertensive rats, than in normotensive rats. Microinjection of the ? receptor agonist [D-Ala(2) , MePhe(4) , Gly(5) -ol]-enkephalin (DAMGO), but not that of the ?2A -adrenoceptor agonist guanfacine, into the NTS of normotensive rats increased ? receptor/?2A -adrenoceptor heterodimer formation and BP elevation. The NO-dependent BP-lowering effect of ?2A -adrenoceptor agonists was blunted following increased formation of ? receptor/?2A -adrenoceptor heterodimers in the NTS of hypertensive rats and DAMGO-treated normotensive rats.Increases in endogenous ? receptor agonists in the NTS induced ? receptor/?2A -adrenoceptor heterodimer formation and reduced the NO-dependent depressor effect of ?2A -adrenoceptor agonists. This process could contribute to the pathogenesis of hypertension.

SUBMITTER: Sun GC

PROVIDER: S-EPMC4409903 | biostudies-other | 2015 May

REPOSITORIES: biostudies-other

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GPCR dimerization in brainstem nuclei contributes to the development of hypertension.

Sun Gwo-Ching GC Ho Wen-Yu WY Chen Bo-Rung BR Cheng Pei-Wen PW Cheng Wen-Han WH Hsu Mei-Chi MC Yeh Tung-Chen TC Hsiao Michael M Lu Pei-Jung PJ Tseng Ching-Jiunn CJ

British journal of pharmacology 20150317 10

<h4>Background and purpose</h4>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.<h ...[more]

PMID: 25573074

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Project description:ImportanceThe neurobiologic basis of late-life depressive symptoms is not well understood.ObjectiveTo test the hypothesis that neurodegeneration and neuronal density in brainstem aminergic nuclei are related to late-life depressive symptoms. DESIGN, SETTING, PARTICIPANTS, AND EXPOSURE: Longitudinal clinicopathological cohort study at residences of participants in the Chicago, Illinois, metropolitan area. Participants included 124 older persons without dementia in the Rush Memory and Aging Project who had annual evaluations for a mean (SD) of 5.7 (2.8) years, died, and underwent a postmortem neuropathological examination that provided estimates of the densities of Lewy bodies, neurofibrillary tangles, and aminergic neurons in the locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area.Main outcomes and measuresThe number of depressive symptoms (mean [SD], 1.61 [1.48]; range, 0-6; skewness, 0.94) on the Center for Epidemiological Studies Depression Scale averaged across annual evaluations.ResultsBrainstem Lewy bodies were associated with depressive symptoms, and the association was attenuated in those taking antidepressant medication. Brainstem tangles were associated with more depressive symptoms in those without cognitive impairment but with fewer symptoms in those with mild cognitive impairment. Lower density of tyrosine hydroxylase-immunoreactive neurons in the ventral tegmental area was robustly associated with a higher level of depressive symptoms (mean [SE] estimate, -0.014 [0.003]; P < .001; 16.3% increase in adjusted R2). The association was not modified by medication use or cognitive impairment. Neither tyrosine hydroxlyase-immunoreactive neurons in the locus ceruleus nor tryptophan hydroxlyase-immunoreactive neurons in the dorsal raphe nucleus were related to depressive symptoms.Conclusions and relevanceThe results suggest that the mesolimbic dopamine system, especially the ventral tegmental area, has an important role in late-life depressive symptoms.

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GPCR dimerization in brainstem nuclei contributes to the development of hypertension.

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GPCR dimerization in brainstem nuclei contributes to the development of hypertension.

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