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

P2X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。在疼痛反应的产生、神经性疼痛的发展和血压的维持过程中，P2X受体介导ATP的快速生物反应。P2X受体在结构上与其他配体门控离子通道家族不同，因为其功能通道是三聚体的，由三个成孔亚基联合形成。人类基因组编码7个孔形成亚基（P2X1-7），除P2X6外，所有亚基都能形成功能同源体。在啮齿类动物中，有明确的证据表明存在功能性异源P2X受体（由不同亚基形成，例如P2X2/3），但很少有证据表明存在人类P2X受体。这些信息对于理解人体组织中ATP反应的分子基础，以及确保在药物开发过程中使用有用的受体替代物至关重要。该学生将获得人类P2X异聚体存在的生化和功能证据，最初探索人类P2X4受体的异聚化，P2X4受体是疼痛和血压治疗的目标。该项目提供膜片钳电生理学、钙成像、免疫沉淀和western blot、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。

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.