Role of tyrosine kinase activity in alpha-adrenergic inhibition of the beta-adrenergically regulated L-type Ca(2+) current in guinea-pig ventricular myocytes.
Role of tyrosine kinase activity in alpha-adrenergic inhibition of the beta-adrenergically regulated L-type Ca(2+) current in guinea-pig ventricular myocytes.
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酪氨酸激酶活性在α-肾上腺素能抑制豚鼠心室肌细胞中β-肾上腺素调节的L-型Ca(2)电流中的作用。
DOI：
10.1111/j.1469-7793.2001.00779.x
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Harvey,RD
中科院分区：
文献类型：
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作者：
Belevych,AE;Nulton-Persson,A;Sims,C;Harvey,RD
1本研究的目的是探讨酪氨酸激酶活性有助于心肌细胞α1-肾上腺素能抑制β-肾上腺素能反应的假说。我们通过使用全细胞膜片钳技术研究急性分离的成年豚鼠心室肌细胞L-型Ca 2+电流的药理学调节来解决这个问题。2选择性α1-肾上腺素能受体激动剂甲氧胺对基础L-型Ca 2+电流没有影响。甲氧胺对H2组胺受体激活介导的cAMP依赖性Ca 2+电流刺激也无影响。然而，甲氧胺确实抑制β肾上腺素能受体激活介导的cAMP依赖性Ca 2+电流刺激。甲氧胺抑制β-肾上腺素能调节的钙电流的能力被酪氨酸激酶抑制剂染料木黄酮和熏衣草素A显著拮抗。3甲氧胺的抑制作用也被磷酸酪氨酸磷酸酶抑制剂过钒酸盐（PVN）模拟。PVN对基础钙电流和组胺刺激的钙电流无影响，但对β-肾上腺素能受体激活的钙电流有抑制作用。此外，PVN抑制β-肾上腺素能刺激Ca 2+电流的能力被拉曲菌素A拮抗。4这些结果与豚鼠心室肌细胞中β-肾上腺素能反应的α-肾上腺素能抑制涉及酪氨酸激酶依赖性信号通路的结论一致。甲氧胺和PVN拮抗β-肾上腺素能受体（而非H2组胺）激活介导的cAMP依赖性反应的事实表明，α-肾上腺素能刺激和酪氨酸激酶活性的抑制作用是在β-肾上腺素能受体水平。
1The purpose of this study was to investigate the hypothesis that tyrosine kinase activity contributes to α1‐adrenergic inhibition of β‐adrenergic responses in cardiac myocytes. We addressed this question by studying the pharmacological regulation of the L‐type Ca2+current in acutely isolated adult guinea‐pig ventricular myocytes using the whole‐cell patch‐clamp technique.2The selective α1‐adrenergic receptor agonist methoxamine had no effect on the basal L‐type Ca2+current. Methoxamine also had no effect on cAMP‐dependent stimulation of the Ca2+current mediated by H2histamine receptor activation. However, methoxamine did inhibit cAMP‐dependent stimulation of the Ca2+current mediated by β‐adrenergic receptor activation. The ability of methoxamine to inhibit β‐adrenergic regulation of the Ca2+current was significantly antagonized by the tyrosine kinase inhibitors genistein and lavendustin A.3The inhibitory effect of methoxamine was also mimicked by the phosphotyrosine phosphatase inhibitor pervanadate (PVN). PVN had no effect on basal Ca2+current or Ca2+current stimulated by histamine, but it did inhibit Ca2+current stimulated by β‐adrenergic receptor activation. Furthermore, the ability of PVN to inhibit β‐adrenergic stimulation of the Ca2+current was antagonized by lavendustin A.4These results are consistent with the conclusion that in guinea‐pig ventricular myocytes α‐adrenergic inhibition of β‐adrenergic responses involves a tyrosine kinase‐dependent signalling pathway. The fact that methoxamine and PVN antagonized cAMP‐dependent responses mediated by β‐adrenergic, but not H2histamine, receptor activation suggests that the inhibitory effect of α‐adrenergic stimulation and tyrosine kinase activity is at the level of the β‐adrenergic receptor.