Inhibition of protein kinase A and cyclic AMP response element (CRE)-specific transcription factor binding by delta9-tetrahydrocannabinol (delta9-THC): a putative mechanism of cannabinoid-induced immune modulation.
Inhibition of protein kinase A and cyclic AMP response element (CRE)-specific transcription factor binding by delta9-tetrahydrocannabinol (delta9-THC): a putative mechanism of cannabinoid-induced immune modulation.
复制标题
δ9-四氢大麻酚 (delta9-THC) 对蛋白激酶 A 和环 AMP 反应元件 (CRE) 特异性转录因子结合的抑制：大麻素诱导的免疫调节的假定机制。
DOI：
10.1016/s0006-2952(97)82441-0
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发表时间：
1997
影响因子：
5.8
通讯作者：
Kaminski,NE
中科院分区：
文献类型：
--
作者：
Koh,WS;Crawford,RB;Kaminski,NE
Δ9-Tetrahydrocannabinol （Δ9-THC）结合大麻素受体诱导抑制腺苷酸环化酶活性通过百日咳毒素敏感的gtp结合蛋白的参与。在这项研究中，我们研究了Δ9-THC减少环AMP （cAMP）形成对小鼠脾细胞中腺苷酸环化酶远端cAMP通路信号事件的影响。Δ9-THC处理使福斯克林诱导的蛋白激酶a （PKA）活性显著降低，且与浓度相关。这种激酶活性的降低是由于cAMP形成的抑制，而不是通过对激酶的直接影响，因为PKA活性在外源cAMP存在下不能通过Δ9-THC直接调节。PKA在该信号通路中的主要作用之一是激活转录因子，随后结合cAMP应答元件（CRE），这些元件存在于cAMP应答基因的启动子区域。在目前的研究中，我们观察到福斯克林处理脾细胞导致反式作用因子与CRE结合的快速激活，该激活在30-60分钟达到峰值，并且在Δ9-THC存在下其结合受到浓度依赖性的抑制。与福斯克林一样，有丝分裂刺激包括抗cd3单抗或佛博尔酯加离子霉素处理脾细胞诱导CRE结合活性，其在60分钟左右达到最大，并被Δ9-THC处理抑制。综上所述，这些数据表明camp介导的信号转导被Δ9-THC抑制，从而导致结合CRE调控位点的转录因子的激活减少。
Δ9-Tetrahydrocannabinol (Δ9-THC) binding to cannabinoid receptors induces an inhibition in adenylate cyclase activity through the engagement of a pertussis toxin-sensitive GTP-binding protein. In this study we investigated the ramifications of decreased cyclic AMP (cAMP) formation by Δ9-THC on signaling events through the cAMP pathway distal to adenylate cyclase in mouse splenocytes. Δ9-THC treatment produced a marked and concentration-related decrease in forskolin-inducible protein kinase A (PKA) activity. This decrease in kinase activity was due to an inhibition in cAMP formation and not through a direct effect on the kinase as evidenced by the fact that PKA activity could not be modulated directly by Δ9-THC in the presence of exogenous cAMP. One of the primary roles of PKA in this signaling pathway is to activate transcription factors for subsequent binding to cAMP response elements (CRE) present in the promoter region of cAMP-responsive genes. In the present studies, we observed that forskolin treatment of splenocytes resulted in a rapid activation of trans-acting factor binding to the CRE, which peaked at 30–60 min and whose binding was repressed concentration dependently in the presence of Δ9-THC. As with forskolin, mitogenic stimulation including anti-CD3 mAb or phorbol ester plus ionomycin treatment of splenocytes induced CRE binding activity, which was maximal around 60 min and was suppressed by Δ9-THC treatment. In conclusion, these data indicate that cAMP-mediated signal transduction is inhibited by Δ9-THC and consequently leads to a decrease in the activation of transcription factors that bind to CRE regulatory sites.