Mixing it up: heteromultimerisation of P2X receptor and its impact on ion channel properties and pharmacology

混合起来：P2X 受体的异多聚化及其对离子通道特性和药理学的影响

• 批准号: 2060462
• 金额: --
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2060462
• 关键词: Mixing; up; heteromultimerisation; P2X; receptor

P2X receptors are ligand-gated ion channels activated by the neurotransmitter extracellular adenosine 5'-triphosphate (ATP). P2X receptors mediate fast biological responses to ATP during the generation of pain responses, development of neuropathic pain and the maintenance of blood pressure. P2X receptors are structurally unusual amongst other ligand-gated ion channel families in that the functional channels are trimeric, formed by the association of three pore-forming subunits. The human genome encodes seven pore-forming subunits (P2X1-7) with all, expect P2X6, capable of forming functional homomers. In rodents, there is clear evidence for the existence of functional heteromeric P2X receptors (formed from different subunits e.g. P2X2/3) but little evidence exists for human P2X receptors. This information is critical for understanding the molecular basis of ATP responses in human tissues, and ensuring the use of useful receptor surrogates during drug development.This studentship will gain biochemical and functional evidence for the existence of human P2X heteromers, initially exploring heteromerisation of the human P2X4 receptor, a target for pain and blood pressure therapies. The project offers advanced training in patch-clamp electrophysiology, calcium imaging, immunoprecipitation and western blot, mutagenesis and molecular modelling. The project is suited to those interesting in receptor pharmacology and drug discovery.

P2 X受体是由神经递质细胞外腺苷5 '-三磷酸（ATP）激活的配体门控离子通道。P2 X受体在疼痛反应的产生、神经性疼痛的发展和血压的维持期间介导对ATP的快速生物反应。P2 X受体在其他配体门控离子通道家族中在结构上是不寻常的，因为功能通道是三聚体的，由三个孔形成亚基缔合形成。人类基因组编码7个孔形成亚基（P2 X1 -7），除P2 X6外，所有亚基都能够形成功能性同源体。在啮齿类动物中，有明确的证据表明存在功能性异聚体P2 X受体（由不同的亚基形成，例如P2 X2/3），但几乎没有证据表明存在人类P2 X受体。这些信息对于理解人体组织中ATP反应的分子基础至关重要，并确保在药物开发过程中使用有用的受体替代物。该学生将获得人类P2 X异聚体存在的生物化学和功能证据，初步探索人类P2 X4受体的异聚化，疼痛和血压治疗的靶点。该项目提供膜片钳电生理学、钙成像、免疫沉淀和蛋白质印迹、诱变和分子建模方面的高级培训。该项目适合那些对受体药理学和药物发现感兴趣的人。