Del Valle-Rodríguez Alberto, Calderón Eva, Ruiz Myriam, Ordoñez Antonio, López-Barneo José, Ureña Juan
Laboratorio de Investigaciones Biomédicas and Unidad de Cirugía Cardiovascular, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, E-41013, Seville, Spain.
Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4316-21. doi: 10.1073/pnas.0508781103. Epub 2006 Mar 7.
Voltage-gated Ca(2+) channels in arterial myocytes can mediate Ca(2+) release from the sarcoplasmic reticulum and, thus, induce contraction without the need of extracellular Ca(2+) influx. This metabotropic action of Ca(2+) channels (denoted as calcium-channel-induced calcium release or CCICR) involves activation of G proteins and the phospholipase C-inositol 1,4,5-trisphosphate pathway. Here, we show a form of vascular tone regulation by extracellular ATP that depends on the modulation of CCICR. In isolated arterial myocytes, ATP produced facilitation of Ca(2+)-channel activation and, subsequently, a strong potentiation of CCICR. The facilitation of L-type channel still occurred after full blockade of purinergic receptors and inhibition of G proteins with GDPbetaS, thus suggesting that ATP directly interacts with Ca(2+) channels. The effects of ATP appear to be highly selective, because they were not mimicked by other nucleotides (ADP or UTP) or vasoactive agents, such as norepinephrine, acetylcholine, or endothelin-1. We have also shown that CCICR can trigger arterial cerebral vasoconstriction in the absence of extracellular calcium and that this phenomenon is greatly facilitated by extracellular ATP. Although, at low concentrations, ATP does not induce arterial contraction per se, this agent markedly potentiates contractility of partially depolarized or primed arteries. Hence, the metabotropic action of L-type Ca(2+) channels could have a high impact on vascular pathophysiology, because, even in the absence of Ca(2+) channel opening, it might mediate elevations of cytosolic Ca(2+) and contraction in partially depolarized vascular smooth muscle cells exposed to small concentrations of agonists.
动脉肌细胞中的电压门控性Ca(2+)通道可介导肌浆网释放Ca(2+)，从而在无需细胞外Ca(2+)内流的情况下诱导收缩。Ca(2+)通道的这种促代谢作用（称为钙通道诱导的钙释放或CCICR）涉及G蛋白和磷脂酶C-肌醇1,4,5-三磷酸途径的激活。在此，我们展示了一种细胞外ATP对血管张力的调节形式，该调节取决于CCICR的调节作用。在分离的动脉肌细胞中，ATP促进了Ca(2+)通道的激活，随后显著增强了CCICR。在用GDPβS完全阻断嘌呤能受体并抑制G蛋白后，L型通道的促进作用仍然存在，因此表明ATP直接与Ca(2+)通道相互作用。ATP的作用似乎具有高度选择性，因为其他核苷酸（ADP或UTP）或血管活性物质，如去甲肾上腺素、乙酰胆碱或内皮素-1，均无法模拟其作用。我们还表明，在没有细胞外钙的情况下，CCICR可触发脑动脉血管收缩，并且细胞外ATP可极大地促进这一现象。尽管在低浓度时，ATP本身不会诱导动脉收缩，但该物质可显著增强部分去极化或预激动脉的收缩性。因此，L型Ca(2+)通道的促代谢作用可能对血管病理生理学具有重大影响，因为即使在Ca(2+)通道未开放的情况下，它也可能介导暴露于低浓度激动剂的部分去极化血管平滑肌细胞中胞质Ca(2+)的升高和收缩。
