L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor.
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.
['Masukawa|Daiki|D|', 'Koga|Motokazu|M|', 'Sezaki|Anna|A|', 'Nakao|Yuka|Y|', 'Kamikubo|Yuji|Y|', 'Hashimoto|Tatsuo|T|', 'Okuyama-Oki|Yuki|Y|', 'Aladeokin|Aderemi Caleb|AC|', 'Nakamura|Fumio|F|', 'Yokoyama|Utako|U|', 'Wakui|Hiromichi|H|', 'Ichinose|Hiroshi|H|', 'Sakurai|Takashi|T|', 'Umemura|Satoshi|S|', 'Tamura|Koichi|K|', 'Ishikawa|Yoshihiro|Y|', 'Goshima|Yoshio|Y|']
D000818:Animals D002118:Calcium D002478:Cells, Cultured D048049:Extracellular Signal-Regulated MAP Kinases D005136:Eye Proteins D007980:Levodopa D008562:Membrane Glycoproteins D051379:Mice D018345:Mice, Knockout D009129:Muscle Tonus D009131:Muscle, Smooth, Vascular D010656:Phenylephrine D010766:Phosphorylation D018340:Receptors, Adrenergic, alpha-1 D043562:Receptors, G-Protein-Coupled D015398:Signal Transduction D014662:Vasoconstrictor Agents
Cell Biology Pharmacology Vascular Biology