| RRC ID |
52392
|
| Author |
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.
|
| Title |
L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor.
|
| Journal |
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.
|
| Volume |
2(18)
|
| Published |
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
|
| Times Cited |
3
|
| Resource |
| Human and Animal Cells |
293(RCB1637) |
