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内源性大麻素肽 RVD- 血红蛋白素是 TRPV1 通道阻断剂。

The Endocannabinoid Peptide RVD-Hemopressin Is a TRPV1 Channel Blocker.

机构信息

Facultad de Ciencias Agrarias y Forestales, Universidad Católica del Maule, Talca 3460000, Chile.

Center for Bioinformatics and Integrative Biology (CBIB), Universidad Andrés Bello, Santiago 8370146, Chile.

出版信息

Biomolecules. 2024 Sep 8;14(9):1134. doi: 10.3390/biom14091134.

DOI:10.3390/biom14091134
PMID:39334900
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11430712/
Abstract

Neurotransmission is critical for brain function, allowing neurons to communicate through neurotransmitters and neuropeptides. RVD-hemopressin (RVD-Hp), a novel peptide identified in noradrenergic neurons, modulates cannabinoid receptors CB1 and CB2. Unlike hemopressin (Hp), which induces anxiogenic behaviors via transient receptor potential vanilloid 1 (TRPV1) activation, RVD-Hp counteracts these effects, suggesting that it may block TRPV1. This study investigates RVD-Hp's role as a TRPV1 channel blocker using HEK293 cells expressing TRPV1-GFP. Calcium imaging and patch-clamp recordings demonstrated that RVD-Hp reduces TRPV1-mediated calcium influx and TRPV1 ion currents. Molecular docking and dynamics simulations indicated that RVD-Hp interacts with TRPV1's selectivity filter, forming stable hydrogen bonds and van der Waals contacts, thus preventing ion permeation. These findings highlight RVD-Hp's potential as a therapeutic agent for conditions involving TRPV1 activation, such as pain and anxiety.

摘要

神经传递对于大脑功能至关重要，使神经元能够通过神经递质和神经肽进行通讯。RVD-hemopressin（RVD-Hp）是在去甲肾上腺素能神经元中鉴定出的一种新型肽，调节大麻素受体 CB1 和 CB2。与通过瞬时受体电位香草素 1（TRPV1）激活诱导焦虑行为的 hemopressin（Hp）不同，RVD-Hp 抵消了这些作用，表明它可能阻断 TRPV1。本研究使用表达 TRPV1-GFP 的 HEK293 细胞研究了 RVD-Hp 作为 TRPV1 通道阻断剂的作用。钙成像和膜片钳记录表明，RVD-Hp 减少了 TRPV1 介导的钙内流和 TRPV1 离子电流。分子对接和动力学模拟表明，RVD-Hp 与 TRPV1 的选择性过滤器相互作用，形成稳定的氢键和范德华接触，从而阻止离子渗透。这些发现强调了 RVD-Hp 作为涉及 TRPV1 激活的疾病的治疗剂的潜力，例如疼痛和焦虑。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ca/11430712/8378e1555daf/biomolecules-14-01134-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ca/11430712/1f8f14512655/biomolecules-14-01134-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ca/11430712/1332075d44b1/biomolecules-14-01134-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ca/11430712/2bd3bbba757c/biomolecules-14-01134-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ca/11430712/f2f64ff57db8/biomolecules-14-01134-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ca/11430712/8378e1555daf/biomolecules-14-01134-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ca/11430712/1f8f14512655/biomolecules-14-01134-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ca/11430712/1332075d44b1/biomolecules-14-01134-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ca/11430712/2bd3bbba757c/biomolecules-14-01134-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ca/11430712/f2f64ff57db8/biomolecules-14-01134-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5ca/11430712/8378e1555daf/biomolecules-14-01134-g005.jpg

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本文引用的文献

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Nat Struct Mol Biol. 2024 Sep;31(9):1377-1385. doi: 10.1038/s41594-024-01299-2. Epub 2024 May 2.
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Insights from molecular dynamics simulations of TRPV1 channel modulators in pain.TRPV1 通道调节剂在疼痛中的分子动力学模拟研究进展。
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Molecular Dynamic Simulations Reveal the Activation Mechanisms of Oxidation-Induced TRPV1.分子动力学模拟揭示氧化诱导 TRPV1 的激活机制。
Int J Mol Sci. 2023 May 31;24(11):9553. doi: 10.3390/ijms24119553.
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Human TRPV1 structure and inhibition by the analgesic SB-366791.人类 TRPV1 结构和镇痛剂 SB-366791 的抑制作用。
Nat Commun. 2023 Apr 28;14(1):2451. doi: 10.1038/s41467-023-38162-9.
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Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia.靶向 TRPV1 外孔的正变构调节剂的结构导向肽工程，用于持久的镇痛。
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J Biol Chem. 2021 Sep;297(3):101022. doi: 10.1016/j.jbc.2021.101022. Epub 2021 Jul 30.
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Heat-dependent opening of TRPV1 in the presence of capsaicin.辣椒素存在时 TRPV1 的热依赖性开放。
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