Regulation of calcium by delta9-tetrahydrocannabinol

δ9-四氢大麻酚对钙的调节

• 批准号: 6691195
• 负责人: GAUTHAM K RAO
• 金额: $ 2.74万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-16 至 2006-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6691195
• 关键词: T lymphocyte; autoradiography; calcium; calcium flux; calmodulin dependent protein kinase; cannabinoids; enzyme linked immunosorbent assay; gel mobility shift assay; interleukin 2; laboratory mouse; lymphocyte proliferation; predoctoral investigator; protein kinase C; receptor expression

DESCRIPTION (provided by applicant): Previous studies from this and other laboratories have demonstrated that delta9-tetrahydrocannabinol (delta9-THC), the primary psychoactive constituent in marijuana, can inhibit the expression of interleukin (IL)-2 by activated T cells. However, it remains unclear what role the cannabinoid receptors play in the regulation of IL-2 production by cannabinoids. Here, experiments were performed in murine splenic T cells or human T cell lines, HPB-ALL and Jurkat E6-1. The splenic T cells express both CB1 and CB2 receptor transcripts whereas the human T cells only express CB2 transcripts. Moreover, while HPB-ALL cells express normal CB2 receptors, the Jurkat E6-1 cells express dysfunctional CB2 receptors. Preliminary data using these cell models suggest that delta9-THC may inhibit IL-2 production via a premature rise in intracellular calcium ([Ca2+]i) in a cannabinoid receptor dependent manner. This research will be further pursued with the hypothesis that the inhibition of interleukin-2 expression by delta9-THC involves cannabinoid receptor-dependent elevation of [Ca((]i activation of calcium-dependent enzymes, protein kinase C (PKC) and calcium-dependent calmodulin kinase II (CaMKII), and modulation of nuclear factor of activated T cells (NFAT) activation. Future studies will be performed in the splenic T cells or HPB-ALL cells with three specific aims (SA). SA1) Investigation of the mechanism of [Ca2+]i elevation by ((-THC. SA2) Characterization of the effect of delta9-THC on PKC and CaMKII activation. SA3) Examination of the effect of delta9-THC-mediated elevation in [Ca2+]i on NFAT activation and IL-2 expression.

描述（由申请人提供）： 该实验室和其他实验室之前的研究表明，大麻中主要的精神活性成分 delta9-四氢大麻酚 (delta9-THC) 可以抑制激活的 T 细胞表达白细胞介素 (IL)-2。然而，目前尚不清楚大麻素受体在大麻素产生 IL-2 的调节中发挥什么作用。在此，实验在鼠脾 T 细胞或人 T 细胞系 HPB-ALL 和 Jurkat E6-1 中进行。脾 T 细胞同时表达 CB1 和 CB2 受体转录本，而人类 T 细胞仅表达 CB2 转录本。此外，虽然 HPB-ALL 细胞表达正常的 CB2 受体，但 Jurkat E6-1 细胞表达功能失调的 CB2 受体。使用这些细胞模型的初步数据表明，delta9-THC 可能以大麻素受体依赖性方式通过细胞内钙 ([Ca2+]i) 的过早升高来抑制 IL-2 的产生。这项研究将进一步进行以下假设：delta9-THC 对白细胞介素 2 表达的抑制涉及大麻素受体依赖性升高 [Ca((]i) 钙依赖性酶、蛋白激酶 C (PKC) 和钙依赖性钙调蛋白激酶 II (CaMKII) 的激活，以及激活 T 细胞核因子 (NFAT) 激活的调节。未来的研究 将在脾 T 细胞或 HPB-ALL 细胞中进行，具有三个特定目标 (SA)。 SA1) 通过 ((-THC) 研究 [Ca2+]i 升高的机制。SA2) 描述 delta9-THC 对 PKC 和 CaMKII 激活的影响。SA3) 检查 delta9-THC 介导的 [Ca2+]i 升高对 NFAT 激活和 IL-2 的影响 表达。