Ballard C, Schaffer S
Department of Pharmacology, University of South Alabama, Mobile 36688, USA.
J Mol Cell Cardiol. 1996 Jan;28(1):11-7. doi: 10.1006/jmcc.1996.0002.
The Na+/Ca2+ exchanger plays an important role in the maintenance of calcium homeostasis in the heart. Therefore, factors which regulate the exchanger have a significant impact on cardiac function. Previously, we showed that the non-hydrolysable GTP analog, 5'guanylyl imidodiphosphate [Gpp(NH)p], stimulates Na+/Ca2+ exchange activity, implying the involvement of a G protein in exchanger regulation. In this study, we examined the effect of G protein agonists on Na+/Ca2+ exchanger activity. Isoproterenol, a Gs agonist, had no effect on exchanger activity. Likewise, the Gi agonist, carbachol, did not influence Na+/Ca2+ exchanger activity. Since these G proteins couple to the adenylate cyclase system, it would appear that cAMP-linked events do not regulate the Na+/Ca2+ exchanger. We next examined the influence of Gq-linked agonists on exchanger activity. Phenylephrine, an alpha 1-adrenergic agonist, increased Na+/Ca2+ exchanger activity up to 111% with an EC50 of 21 microM. Moreover, the Na+/Ca2+ exchanger activity was enhanced by angiotensin II and endothelin 1, which caused maximal stimulation of exchanger activity up to 125% and 211%, respectively. The selective protein kinase C inhibitor chelerythrine significantly attenuated the ability of phenylephrine and angiotensin II to stimulate the Na+/Ca2+ exchanger. In addition, the protein kinase C activator, phorbol 12-myristate 13-acetate, stimulated exchanger activity by 32%, raising the possibility that all three Gq agonists mediate their actions in part through the promotion of phospholipase C activity and the subsequent activation of protein kinase C. The contribution of Na+/Ca2+ exchange to the actions of phenylephrine, angiotensin II, and endothelin 1 is discussed.
钠钙交换体在维持心脏钙稳态方面发挥着重要作用。因此，调节该交换体的因素对心脏功能有显著影响。此前，我们发现不可水解的GTP类似物5'-鸟苷酰亚胺二磷酸[Gpp(NH)p]可刺激钠钙交换活性，这意味着G蛋白参与了交换体的调节。在本研究中，我们检测了G蛋白激动剂对钠钙交换体活性的影响。Gs激动剂异丙肾上腺素对交换体活性无影响。同样，Gi激动剂卡巴胆碱也不影响钠钙交换体活性。由于这些G蛋白与腺苷酸环化酶系统偶联，似乎cAMP相关事件并不调节钠钙交换体。接下来，我们检测了与Gq偶联的激动剂对交换体活性的影响。α1肾上腺素能激动剂去氧肾上腺素可使钠钙交换体活性增加高达111%，EC₅₀为21μM。此外，血管紧张素II和内皮素-1可增强钠钙交换体活性，分别使交换体活性最大刺激至125%和211%。选择性蛋白激酶C抑制剂白屈菜红碱显著减弱了去氧肾上腺素和血管紧张素II刺激钠钙交换体的能力。此外，蛋白激酶C激活剂佛波醇12-肉豆蔻酸酯13-乙酸酯可使交换体活性提高32%，这增加了所有三种Gq激动剂部分通过促进磷脂酶C活性及随后激活蛋白激酶C来介导其作用的可能性。本文讨论了钠钙交换对去氧肾上腺素、血管紧张素II和内皮素-1作用的贡献。
