Tyrosine kinase inhibitors and ATP modulate the conversion of smooth muscle L-type Ca2+ channels toward a second open state
Tyrosine kinase inhibitors and ATP modulate the conversion of smooth muscle L-type Ca2+ channels toward a second open state
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DOI：
10.1096/fj.05-5049fje
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发表时间：
2006-07-01
期刊：
影响因子：
4.8
通讯作者：
Kajioka, Shunichi
中科院分区：
文献类型：
--
作者：
Nakayama, Shinsuke;Ito, Yasushi;Kajioka, Shunichi
平滑和心脏L-型Ca 2+通道的特性在几个生理方面有显著差异，包括交感神经调制。为了评估可能的潜在机制，我们应用全细胞膜片钳技术，豚鼠逼尿肌平滑肌细胞，在实践中只观察到L型钙通道电流。在去极化到大的正电位期间，大多数L型Ca 2+通道的构象从正常（O-1）转换为第二开放状态（O-2），其在去极化期间几乎不失活。染料木黄酮，一种已知的酪氨酸激酶抑制剂，细胞外应用显着衰减的电压依赖性转换的Ca 2+通道O-2，伴随着减少的可用性，而染料木黄酮，一种无活性的类似物，几乎没有影响。在没有ATP的情况下，在贴片移液管，细胞内应用染料木素或tyrphostin-47抑制转换为O-2。计算机计算表明，O-1加速到失活状态定性重建了ATP拮抗PTK抑制剂的独特作用。我们的结论是，在正常条件下，平滑肌L型Ca ~（2+）通道已经受到酪氨酸激酶和ATP相关机制的调节，从而很容易实现第二次转换，产生类似于在β-肾上腺素受体刺激时心肌细胞中的L型Ca ~（2+）电流的电压依赖性调节。
Properties of smooth and cardiac L-type Ca2+ channels differ prominently in several physiological aspects, including sympathetic modulation. To assess the possible underlying mechanisms, we applied the whole cell patch-clamp technique to guinea pig detrusor smooth muscle cells, in which only L-type Ca2+ channel currents are observed in practice. During depolarization to large positive potentials, the conformation of the majority of L-type Ca2+ channels is converted from the normal (O-1) to a second open state (O-2), which undergoes little inactivation during depolarization. Extracellular application of genistein, a known tyrosine kinase inhibitor, significantly attenuated the voltage-dependent conversion of Ca2+ channels to O-2, accompanied by reduction of availability, whereas genistin, an inactive analog, had little effect. In the absence of ATP in the patch pipette, intracellular application of either genistein or tyrphostin-47 suppressed the conversion to O-2. Computer calculation revealed that the acceleration of the O-1 to an inactivated state qualitatively reconstructs the unique effects of PTK inhibitors antagonized by ATP. We concluded that under normal conditions smooth muscle L-type Ca2+ channels are already modulated by tyrosine-kinase and ATP-related mechanism(s) and thereby easily achieve the second conversion, which yields voltage-dependent modulation of L-type Ca2+ current analogous to that in cardiac myocytes during beta-adrenoceptor stimulation.