L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor

JCI Insight. 2017 Sep 21;2(18):e90903. doi: 10.1172/jci.insight.90903.


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.

Keywords: Cell Biology; Pharmacology; Vascular Biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Eye Proteins
  • Gpr143 protein, mouse
  • Membrane Glycoproteins
  • Receptors, Adrenergic, alpha-1
  • Receptors, G-Protein-Coupled
  • Vasoconstrictor Agents
  • Phenylephrine
  • Levodopa
  • Extracellular Signal-Regulated MAP Kinases
  • Calcium