L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor
L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor
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L-DOPA 通过调节血管 α1 肾上腺素能受体来敏化血管舒缩张力
作者：
Masukawa Daiki;Koga Motokazu;Sezaki Anna;Nakao Yuka;Kamikubo Yuji;Hashimoto Tatsuo;Okuyama-Oki Yuki;Aladeokin Aderemi Caleb;Nakamura Fumio;Yokoyama Utako;Wakui Hiromichi;Ichinose Hiroshi;Sakurai Takashi;Umemura Satoshi;Tamura Koichi;Ishikawa Yoshihiro;Gos
血压由外部因素调节，包括去甲肾上腺素，这是一种交感神经递质，通过肾上腺素能受体控制心血管功能。然而，去甲肾上腺素信号的微调系统相对未知。L-3，4-二羟基苯丙氨酸(L-多巴)是儿茶酚胺的前体，通过激活L-多巴受体GPR143而使血管肾上腺素能受体α1增敏。在WT小鼠中，静脉注射ADRA1激动剂苯肾上腺素引起一过性血压升高。这种反应在Gpr143基因缺陷(Gpr143-/y)小鼠中减弱。血管平滑肌细胞中Gpr143的特异性敲除也表现出类似的表型，表明L多巴直接调控血管平滑肌细胞中的ADRA1信号转导。单用纳米分子浓度的L多巴对VSMC无影响，但可增强苯肾上腺素引起的血管收缩和细胞内钙离子反应。苯肾上腺素也增强了WT小鼠培养的VSMCs细胞外信号调节蛋白的磷酸化，但不是Gpr143-/y小鼠。在WT小鼠中，血压在从日光休息到暗活动阶段的转变过程中升高。在Gpr143-/y小鼠中没有观察到这种升高。综上所述，我们的发现为L-DOPA/GPR143信号通过敏化血管ADRA1而对交感神经传递发挥前体调控作用提供了证据。
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.