The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons.
The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons.
复制标题
DOI：
10.1016/j.phrs.2012.08.002
复制
发表时间：
2012-11
影响因子：
9.3
通讯作者：
Straiker, A.
中科院分区：
文献类型：
--
作者：
Murataeva, N.;Mackie, K.;Straiker, A.
G蛋白偶联受体CB 1和CB 2是大麻的精神活性成分的靶标，其中主要是Δ9-THC。它们也是多功能内源性大麻素信号传导系统的关键组分。CB 1和CB 2受体调节多种生理系统，包括镇痛、记忆、情绪、奖赏、食欲和免疫。选择性CB 1和CB 2受体激动剂和拮抗剂的鉴定和表征将有助于理解大麻素受体在这些系统中的精确生理和病理生理作用。这在CB 2的情况下是特别必要的，因为这些受体是稀疏表达的，并且使用传统的免疫细胞化学方法检测有问题。1-丙基-2-甲基-3-（1-萘甲酰基）吲哚（JWH 015）是一种氨基烷基吲哚，已在40多篇已发表的论文中用作“CB 2选择性”激动剂。然而，我们发现JWH 015有效地激活了神经元中的CB 1受体。使用表达CB 1但不表达CB 2受体的小鼠自发性海马神经元，我们发现JWH 015抑制兴奋性突触后电流，EC 50为216 nM。JWH 015抑制在CB 1 −/−培养物的神经元中不存在，并被CB 1拮抗剂SR 141716 [200 nM]逆转。此外，JWH 015部分阻断CB 1介导的DSE（约35%剩余），CB 2拮抗剂AM 630 [1和3 μM]可逆转该作用，表明高浓度的AM 630也可拮抗CB 1受体。我们的结论是，虽然JWH 015是CB 2偏好激动剂，它也激活CB 1受体在实验遇到的浓度。因此，在设计和解释使用JWH 015探测CB 2信号传导的实验时需要考虑JWH 015的CB 1激动作用。
The G protein coupled receptors CB1 and CB2 are targets for the psychoactive constituents of cannabis, chief among them Δ9-THC. They are also key components of the multifunctional endogenous cannabinoid signaling system. CB1 and CB2 receptors modulate a wide variety of physiological systems including analgesia, memory, mood, reward, appetite and immunity. Identification and characterization of selective CB1 and CB2 receptor agonists and antagonists will facilitate understanding the precise physiological and pathophysiological roles of cannabinoid receptors in these systems. This is particularly necessary in the case of CB2 because these receptors are sparsely expressed and problematic to detect using traditional immunocytochemical approaches. 1-Propyl-2-methyl-3-(1-naphthoyl)indole (JWH015) is an aminoalkylindole that has been employed as a “CB2-selective” agonist in more than 40 published papers. However, we have found that JWH015 potently and efficaciously activates CB1 receptors in neurons. Using murine autaptic hippocampal neurons, which express CB1, but not CB2 receptors, we find that JWH015 inhibits excitatory postsynaptic currents with an EC50 of 216 nM. JWH015 inhibition is absent in neurons from CB1−/− cultures and is reversed by the CB1 antagonist, SR141716 [200 nM]. Furthermore, JWH015 partially occludes CB1-mediated DSE (~35% remaining), an action reversed by the CB2 antagonist, AM630 [1 and 3 μM], suggesting that high concentrations of AM630 also antagonize CB1 receptors. We conclude that while JWH015 is a CB2-preferring agonist, it also activates CB1 receptors at experimentally encountered concentrations. Thus, CB1 agonism of JWH015 needs to be considered in the design and interpretation of experiments that use JWH015 to probe CB2-signaling.
登录
查看更多内容
影响因子：
3.5
作者：
Huffman, JW;Zengin, G;Martin, BR
通讯作者：
Martin, BR
DOI：
10.1073/pnas.73.11.4225
发表时间：
1976-01-01
影响因子：
11.1
作者：
FURSHPAN, EJ;MACLEISH, PR;POTTER, DD
通讯作者：
POTTER, DD
影响因子：
4.7
作者：
Hsieh, C;Brown, S;Mackie, K
通讯作者：
Mackie, K
影响因子：
8.6
作者：
Lombard, Catherine;Nagarkatti, Mitzi;Nagarkatti, Prakash
通讯作者：
Nagarkatti, Prakash
影响因子：
4.8
作者：
Anavi-Goffer, Sharon;Baillie, Gemma;Ross, Ruth A.
通讯作者：
Ross, Ruth A.