Molecular physiology and pharmacology of TRESK K2P K+ channels

TRESK K2P K 通道的分子生理学和药理学

• 批准号: 506373940
• 负责人: Professor Dr. Thomas Baukrowitz
• 金额: --
• 依托单位: Physiologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/506373940?language=en
• 关键词: Molecular; physiology; pharmacology; TRESK; K2P

The TRESK potassium ion channel belongs to the multifaceted Two-Pore-Domain Potassium (K2P) channel family, important regulators of cellular excitability, which participate in many physiological and pathophysiological processes from hormone secretion and chemosensation to anaesthesia, neuroprotection and pain. TRESK channels are highly expressed in dorsal root ganglia as well as trigeminal ganglia neurons and involved in pain sensation such as migraine constituting promising pharmacological targets. TRESK currents are strongly regulated by (de)phosphorylation via Calcineurin and several Phosphokinases (e.g. MAPK, PKA and PKC) that target a large cytoplasmic domain unique to the TRESK channel. Furthermore, important cellular lipids including DAG, arachidonic acid, anandamide and 2-AG were found to inhibit TRESK activity but its physiological relevance is unexplored. In addition, many small drug molecules inhibit this channel by a poorly understood mechanism. Finally, TRESK channels have been recently shown to form heteromers with TREK-1 and TREK-2 and these heteromers are involved in certain conditions of migraine. Thus, despite its promising implication in the treatment of pain conditions, the channel is still poorly characterized and TRESK function is not understood mechanistically. Here we propose to apply systematic scanning mutagenesis, cysteine modification, homology modeling and patch-clamp electrophysiology to (1) identify the small molecule and lipid binding sites, (2) gain insight into the nature of the intrinsic TRESK gate regulated by e.g. phosphorylation, and (3) explore the receptor pathways that affect TRESK channels via the release of lipid messengers and (4) characterize TREK/TRESK heteromers with respect to the knowledge gathered here on homomeric TRESK channels. This project therefore aims to promote mechanistic insight into the poorly understood molecular physiology and pharmacology of TRESK channels.

TRESK钾离子通道属于多方面的两孔核钾（K2P）通道家族，这是细胞兴奋性的重要调节剂，这些调节剂参与了许多生理和病理生理过程，从激素分泌和化学效果到麻醉，神经保护和疼痛。 TRESK通道在背根神经节和三叉神经神经元中高度表达，并参与疼痛感觉，例如构成有希望的药理目标的偏头痛。 TRESK电流受（DE）通过钙调神经蛋白和几种磷酸化的（例如MAPK，PKA和PKC）的（DE）磷酸化的强烈调节，这些磷酸化酶（例如MAPK，PKA和PKC）靶向TRESK通道所特有的大细胞质结构域。此外，发现重要的细胞脂质在内，包括DAG，花生四烯酸，Anandamide和2-AG抑制TRESK活性，但其生理相关性尚未探索。此外，许多小型药物分子通过较知的机制抑制了该通道。最后，最近已显示出TRESK通道与Trek-1和Trek-2形成异构体，并且这些异构体参与偏头痛的某些条件。因此，尽管它在疼痛条件的治疗中具有有希望的意义，但该通道的特征仍然很差，而TRESK功能也不是机械理解的。在这里，我们建议将系统的扫描诱变，半胱氨酸修饰，同源性建模和斑块钳电生理学应用于（1）确定小分子和脂质结合位点，（2）可深入了解e.g的内在TRESK GATE的性质。磷酸化和（3）通过释放脂质使者的释放来探索影响TRESK通道的受体途径，并且（4）相对于在此处收集的同源性TRESK通道中收集的知识，tre trek/tresk异构体表征了Trek/Tresk异构体。因此，该项目旨在促进对TRESK通道的分子生理和药理学知识的机械洞察力。