Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions.
Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions.
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DOI：
10.3389/fphar.2022.914651
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发表时间：
2022
影响因子：
5.6
通讯作者：
van Rijn, Richard. M.
中科院分区：
文献类型：
--
作者：
Blaine, Arryn T.;Miao, Yiming;Yuan, Jinling;Palant, Sophia;Liu, Rebecca J. J.;Zhang, Zhong-Yin;van Rijn, Richard. M.
δ-阿片受体 (δOR) 已被认为是多种神经系统和神经精神疾病的治疗靶点，特别是因为 δOR 激动剂被认为是相对于更容易滥用的 µ-阿片受体药物更安全的替代品。然而，δOR 激动剂的临床开发一直充满挑战，部分原因是某些 δOR 激动剂具有癫痫诱发作用。特别是类似于 δOR 选择性激动剂 SNC80 的激动剂具有明确的惊厥活性。仔细检查表明，许多引起癫痫的 δOR 激动剂可有效招募 β-arrestin，但令人惊讶的是，SNC80 在 β-arrestin 1 敲除小鼠中显示出增强的癫痫活性。这一发现使我们推测，也许 β-arrestin 1 对 δOR 激动剂诱发的癫痫发作具有保护作用，而 β-arrestin 2 则有害。为了研究我们的假设，我们在细胞测定和体内野生型以及 β-arrestin 1 和 β-arrestin 2 敲除小鼠的癫痫活性中表征了三种不同的 δOR 激动剂（SNC80、ADL5859、ARM390）。我们还研究了与 β-arrestin 依赖性信号转导相关的下游激酶。我们发现 δOR 激动剂诱导的癫痫发作活动与激动剂的 β-arrestin 2 功效呈强烈正相关，但使用 MEK 抑制剂 SL327 间接抑制 ERK 激活并不能抑制癫痫发作的效力和持续时间。使用和厚朴酚而非 PQR530 抑制 PI3K/AKT/mTOR 信号传导，可减弱 β-arrestin 1 敲除中的 SNC80 癫痫发作持续时间，但和厚朴酚并不能减少野生型小鼠中 SNC80 诱导的癫痫发作。最终，我们的结果表明 β-arrestin 2 与 δOR 激动剂诱导的癫痫发作强度相关，但整体 β-arrestin 1 敲除小鼠是研究其作用机制的较差模型系统。
The δ-opioid receptor (δOR) has been considered as a therapeutic target in multiple neurological and neuropsychiatric disorders particularly as δOR agonists are deemed safer alternatives relative to the more abuse-liable µ-opioid receptor drugs. Clinical development of δOR agonists, however, has been challenging in part due to the seizure-inducing effects of certain δOR agonists. Especially agonists that resemble the δOR-selective agonist SNC80 have well-established convulsive activity. Close inspection suggests that many of those seizurogenic δOR agonists efficaciously recruit β-arrestin, yet surprisingly, SNC80 displays enhanced seizure activity in β-arrestin 1 knockout mice. This finding led us to hypothesize that perhaps β-arrestin 1 is protective against, whereas β-arrestin 2 is detrimental for δOR-agonist-induced seizures. To investigate our hypothesis, we characterized three different δOR agonists (SNC80, ADL5859, ARM390) in cellular assays and in vivo in wild-type and β-arrestin 1 and β-arrestin 2 knockout mice for seizure activity. We also investigated downstream kinases associated with β-arrestin-dependent signal transduction. We discovered that δOR agonist-induced seizure activity strongly and positively correlates with β-arrestin 2 efficacy for the agonist, but that indirect inhibition of ERK activation using the MEK inhibitor SL327 did not inhibit seizure potency and duration. Inhibition of the PI3K/AKT/mTOR signaling with honokiol but not PQR530, attenuated SNC80 seizure duration in β-arrestin 1 knockout, but honokiol did not reduce SNC80-induced seizures in wild-type mice. Ultimately, our results indicate that β-arrestin 2 is correlated with δOR agonist-induced seizure intensity, but that global β-arrestin 1 knockout mice are a poor model system to investigate their mechanism of action.
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三角洲阿片受体激活调节与慢性神经性疼痛相关的情感疼痛和形式特异性疼痛超敏反应。
影响因子：
4.2
作者：
Cahill CM;Holdridge SV;Liu SS;Xue L;Magnussen C;Ong E;Grenier P;Sutherland A;Olmstead MC
通讯作者：
Olmstead MC
影响因子：
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作者：
Alongkronrusmee, Doungkamol;Chiang, Terrance;van Rijn, Richard M
通讯作者：
van Rijn, Richard M
和厚朴酚通过 JAK-STAT3 信号消除神经胶质瘤/胶质母细胞瘤干细胞样细胞，并通过靶向表皮生长因子受体抑制肿瘤进展
影响因子：
5.2
作者：
Fan, Yipu;Xue, Weikang;Zhao, Weijiang
通讯作者：
Zhao, Weijiang
DOI：
10.1124/jpet.119.262717
发表时间：
2020-08-01
影响因子：
3.5
作者：
Dripps, Isaac J.;Chen, Ruizhuo;Jutkiewicz, Emily M.
通讯作者：
Jutkiewicz, Emily M.
影响因子：
5.6
作者：
Cassell, Robert J.;Mores, Kendall L.;van Rijn, Richard M.
通讯作者：
van Rijn, Richard M.