Pharmacological Differences between Native Homomeric Transient Receptor Potential Canonical Type 4 Channels and Heteromeric Transient Receptor Potential Canonical Type 1/4 Channels in Lateral Septal Neurons.
Pharmacological Differences between Native Homomeric Transient Receptor Potential Canonical Type 4 Channels and Heteromeric Transient Receptor Potential Canonical Type 1/4 Channels in Lateral Septal Neurons.
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天然同质瞬态受体潜在典型4型通道和异源瞬态受体电位典型1/4通道的药理差异。
DOI：
10.3390/ph16091291
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发表时间：
2023-09-13
期刊：
影响因子：
--
通讯作者：
Zheng F
中科院分区：
文献类型：
--
作者：
Phelan KD;Shwe UT;Zheng F
鉴于其独特的表达模式及其在许多神经系统疾病中的关键参与，TRPC 1/4/5亚组已成为药物开发的重要目标，一些化合物现已进入临床试验。然而，很少有人知道这个亚家族的TRPC通道在各种天然组织中的确切亚基组成，以及它是否具有功能和药理学意义。在这项研究中，我们研究了位于外侧隔的两种TRPC 4调节剂的作用，其中代谢型谷氨酸受体（mGluR）激动剂诱导的平台电位是由TRPC 1和TRPC 4组成的TRPC通道介导的。使用尖锐电极在脑切片中细胞内记录外侧隔神经元。通过浴灌流应用药物。我们发现，缺乏TRPC 1的小鼠的平台电位由ML 204和La 3+以类似于人工表达系统中的同源TRPC 4通道的方式调节。然而，主要由野生型小鼠外侧隔神经元中的异聚TRPC 1/4通道介导的平台电位被ML 204和La 3+不同地调制。我们的数据表明，天然同聚TRPC 4通道和异聚TRPC 1/4通道在药理学上是不同的，目前有关TRPC 1/4/5的药物开发策略可能需要重新评估。
Given the unique expression patterns and revelations of its critical involvement in a host of neurological disorders, the TRPC1/4/5 subgroup has become an intense target of drug development, and some compounds are now in clinical trials. However, little is known about the exact subunit composition of this subfamily of TRPC channels in various native tissues, and whether it has functional and pharmacological implications. In this study, we investigated the effects of two TRPC4 modulators located in the lateral septum, in which a metabotropic glutamate receptor (mGluR) agonist-induced plateau potential is mediated by TRPC channels composed of TRPC1 and TRPC4. Lateral septal neurons were recorded intracellularly in brain slices using sharp electrodes. Drugs were applied via bath superfusion. We showed that the plateau potential in mice lacking TRPC1 is modulated by ML204 and La3+ in a manner that is like homomeric TRPC4 channels in artificial expression systems. However, the plateau potential that is primarily mediated by heteromeric TRPC1/4 channels in lateral septal neurons in wildtype mice was modulated differently by ML204 and La3+. Our data suggest that native homomeric TRPC4 channels and heteromeric TRPC1/4 channels are pharmacologically distinct, and the current drug development strategy regarding TRPC1/4/5 may need to be reevaluated.
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影响因子：
4.6
作者：
Muraki K;Ohnishi K;Takezawa A;Suzuki H;Hatano N;Muraki Y;Hamzah N;Foster R;Waldmann H;Nussbaumer P;Christmann M;Bon RS;Beech DJ
通讯作者：
Beech DJ
果蝇TRP通道的历史：新通道超家族的诞生。
影响因子：
1.9
作者：
Minke B
通讯作者：
Minke B
影响因子：
4.8
作者：
Miller, Melissa;Shi, Jie;Zhu, Michael X.
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Zhu, Michael X.
影响因子：
4.8
作者：
Jung, S;Mühle, A;Plant, TD
通讯作者：
Plant, TD
影响因子：
5.5
作者：
Freichel, M;Vennekens, R;Flockerzi, V
通讯作者：
Flockerzi, V