RRC ID 52392
著者 Masukawa D, Koga M, Sezaki A, Nakao Y, Kamikubo Y, Hashimoto T, Okuyama-Oki Y, Aladeokin AC, Nakamura F, Yokoyama U, Wakui H, Ichinose H, Sakurai T, Umemura S, Tamura K, Ishikawa Y, Goshima Y.
タイトル L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor.
ジャーナル JCI Insight
Abstract 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.
巻・号 2(18)
公開日 2017-9-21
DOI 10.1172/jci.insight.90903
PII 90903
PMID 28931752
PMC PMC5621878
MeSH Animals Calcium / metabolism Cells, Cultured Extracellular Signal-Regulated MAP Kinases / metabolism Eye Proteins / genetics Eye Proteins / metabolism Levodopa / pharmacology* Membrane Glycoproteins / genetics Membrane Glycoproteins / metabolism Mice Mice, Knockout Muscle Tonus / drug effects* Muscle, Smooth, Vascular / drug effects* Muscle, Smooth, Vascular / metabolism Muscle, Smooth, Vascular / physiology Phenylephrine / pharmacology Phosphorylation Receptors, Adrenergic, alpha-1 / drug effects* Receptors, Adrenergic, alpha-1 / metabolism Receptors, G-Protein-Coupled / genetics Receptors, G-Protein-Coupled / metabolism Signal Transduction Vasoconstrictor Agents / pharmacology
IF 6.205
引用数 3
リソース情報
ヒト・動物細胞 293(RCB1637)