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

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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.