P2X receptor subtypes can be distinguished by their sensitivity to ATP analogues and selective antagonists. We have used chimeras between human P2X1 and P2X2 receptors to address the contribution of the extracellular loop, transmembrane segments and intracellular termini to the action of partial agonists (higher potency and efficacy of BzATP and AP5A at P2X1 compared to P2X2 receptors) and antagonists (NF449 ~ 1,500 fold more potent at P2X1 compared to P2X2). P2X receptors and chimeras were expressed in Xenopus oocytes and currents recorded with TEVC. Replacing the extracellular loop of the P2X1 receptor with that from P2X2 (P2X1-2EXT) produced a receptor that had low sensitivity to NF449 equivalent to that at the WT P2X2 receptor. Sensitivity similar to WT P2X1 receptors was recorded in the reciprocal P2X2-1EXT chimera for NF449. These data show that antagonist sensitivity was conferred by the extracellular loop, and indicates that these chimeras do not result in major conformational changes. In contrast the effectiveness of partial agonists was increased above P2X1 levels for both the loop transfers suggesting interactions with the rest of the receptors played an important role in regulating agonist sensitivity and efficacy. Swapping TM1 increased the efficacy of AP5A and BzATP at P2X1-2TM1 and P2X2-1TM1 chimeras. Replacement of the TM2 region had reciprocal effects on partial agonist efficacy; P2X1-2TM2 showed partial agonist sensitivity similar to that at P2X2 and P2X2-1TM2 showed partial agonist sensitivity intermediate between P2X1 and P2X2. These results suggest a complex interaction between the TMs and the rest of the receptor in regulating partial agonist efficacy. Exchanging the intracellular N- terminus had no effect on agonist potency, but increased partial agonist efficacy at P2X2-1N and decreased it at P2X1-2N chimeras. This demonstrates that potency and efficacy can be independently regulated. Further subdivision of the N- terminus showed amino acid residues 1-16 predominate in the control of efficacy. The C-terminal chimera P2X2-1C had no effect of partial agonist sensitivity, whereas the reciprocal chimera (P2X1-2C) had partial agonist efficacy intermediate between P2X1 and P2X2. Chimeras and point mutations also identified residues in the C-terminus that regulated recovery from channel desensitization. In summary this study shows that interactions between the extracellular, transmembrane and intracellular portions of the P2X receptor regulate channel properties and suggest that transitions to channel opening, the behaviour of the open channel and recovery from the desensitized state can be controlled independently.