期刊
JCI INSIGHT
卷 2, 期 18, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.90903
关键词
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资金
- Ministry of Education, Culture, Sport, Science and Technology (MEXT) of Japan [26460707]
- Foundation of Strategic Research Projects in Private Universities from the Ministry of Education, Culture, Sport, Science and Technology (MEXT) of Japan
- Japanese SRF Grant for Biomedical Research [1565]
- Uehara Memorial Foundation [201320161]
- fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from MEXT [42890001]
- [15H04687]
- [15K21273]
- [15K21271]
- Grants-in-Aid for Scientific Research [26460707, 16H05358, 17K09040, 17K09313, 16K07062, 17K19403, 15H04687] Funding Source: KAKEN
Blood pressure is regulated by extrinsic factors including noradrenaline, the sympathetic neurotransmitter that controls cardiovascular functions through adrenergic receptors. However, the fine-tuning system of noradrenaline signaling is relatively unknown. We here show that L-3,4-dihydroxyphenylalanine (L-DOPA), a precursor of catecholamines, sensitizes the vascular adrenergic receptor alpha1 (ADRA1) through activation of L-DOPA receptor GPR143. In WT mice, intravenous infusion of the ADRA1 agonist phenylephrine induced a transient elevation of blood pressure. This response was attenuated in Gpr143 gene-deficient (Gpr143(-/y)) mice. Specific knockout of Gpr143 in vascular smooth muscle cells (VSMCs) also showed a similar phenotype, indicating that L-DOPA directly modulates ADRA1 signaling in the VSMCs. L-DOPA at nanomolar concentrations alone produced no effect on the VSMCs, but it enhanced phenylephrine-induced vasoconstriction and intracellular Ca2+ responses. Phenylephrine also augmented the phosphorylation of extracellular signal-regulated kinases in cultured VSMCs from WT but not Gpr143(-/y) mice. In WT mice, blood pressure increased during the transition from light-rest to dark-active phases. This elevation was not observed in Gpr143(-/y) mice. Taken together, our findings provide evidence for L-DOPA/GPR143 signaling that exerts precursor control of sympathetic neurotransmission through sensitizing vascular ADRA1.
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