.....................................................................................................3 Acknowledgements ...................................................................................4 Publications arising from this thesis .......................................................5 Prologue ...........................................................................................

There is abundant evidence that extracellular ATP has an important role in pain signaling at both the periphery and in the CNS. The focus of attention now is on the possibility that ATP and its receptor system might play important roles in chronic pathological pain states, particularly in neuropathic pain. Neuropathic pain is often a consequence of nerve injury through surgery, bone compression...

Crystallization of the zebrafish P2X4 receptor in both open and closed states revealed conformational differences in the ectodomain structures, including the dorsal fin and left flipper domains. Here, we focused on the role of these domains in receptor activation, responsiveness to orthosteric ATP analogue agonists, and desensitization. Alanine scanning mutagenesis of the R203-L214 (dorsal fin)...