The stimulatory effect of cannabinoids on calcium uptake is mediated by Gs GTP-binding proteins and CAMP formation
The stimulatory effect of cannabinoids on calcium uptake is mediated by Gs GTP-binding proteins and CAMP formation
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DOI：
10.1159/000068915
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Sarne, Y
中科院分区：
文献类型：
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作者：
Bash, R;Rukovitch, V;Sarne, Y
大麻素是神经抑制药物，通过G(i/o) gtp结合蛋白传递其细胞作用，减少CAMP形成和Ca2+内流。然而，越来越多的证据表明大麻素的刺激作用包括CAMP和细胞质Ca2+浓度的升高。本研究扩展了我们之前的发现，并表明，在N18TG2神经母细胞瘤细胞中，大麻素激动剂去乙酰左旋antradol （DALN）刺激CAMP的形成和Ca2+的摄取。DALN对CAMP形成的刺激作用不能通过阻断Ca2+进入细胞而消除，而其对Ca2+摄取的刺激作用可以通过阻断CAMP依赖性蛋白激酶而消除。此外，通过福斯克林提高CAMP可以刺激钙摄取，而通过离子霉素或KCl提高细胞内Ca2+浓度则不能刺激CAMP的形成。这些发现表明，在大麻素刺激级联中，CAMP的产生先于Ca2+的流入。DALN对钙摄取的刺激作用抵抗百日咳毒素治疗，并通过将抗G(s)抗体引入细胞完全阻断，表明大麻素的刺激活性是由G(s) gtp结合蛋白介导的。相关的细胞刺激活性的DALN大麻素药物的药理学资料进行了讨论。版权所有(C) 2003 S. Karger AG，巴塞尔。
Cannabinoids are neurodepressive drugs that convey their cellular action through G(i/o) GTP-binding proteins which reduce CAMP formation and Ca2+ influx. However, a growing body of evidence indicates that the stimulatory effects of cannabinoids include the elevation in CAMP and cytosolic Ca2+ concentration. The present study expands our previous findings and demonstrates that, in N18TG2 neuroblastoma cells, the cannabinoid agonist desacetyllevonantradol (DALN) stimulates both CAMP formation and Ca2+ uptake. The stimulatory effect of DALN on CAMP formation was not eliminated by blocking Ca2+ entry to the cells, while its stimulatory effect on Ca2+ uptake was abolished by blocking CAMP-dependent protein kinase. Furthermore, elevating CAMP by forskolin stimulated calcium uptake, while elevating the intracellular Ca2+ concentration by ionomycin or KCl failed to stimulate CAMP formation. These findings suggest that CAMP production precedes the influx of Ca2+ in the cannabinoid stimulatory cascade. The stimulatory effect of DALN on calcium uptake resisted pertussis toxin treatment, and was completely blocked by introducing anti-G(s) antibodies into the cells, indicating that the stimulatory activity of cannabinoids is mediated by G(s) GTP-binding proteins. The relevance of the cellular stimulatory activity of DALN to the pharmacological profile of cannabinoid drugs is discussed. Copyright (C) 2003 S. Karger AG, Basel.