Apparent species differences in the kinetic properties of P2X7 receptors

1 Apparent species differences in the responses of recombinant P2X(7) receptors to repeated application of 2'- and 3'-O-(4-benzoylbenzoyl)-ATP (BzATP) have been investigated. 2 Repeated application of 100 mu M BzATP resulted in a progressive increase in current magnitude (current growth) at mouse and human, but not rat P2X(7) receptors. 3 Current growth was thought to reflect progressive dilation of the P2X(7) ion-channel to a pore permeable to large molecules (MW < 900), suggesting that channel dilation was not occurring at the rat P2X(7) receptor. However, 100 mu M BzATP produced a rapid influx of YO-PRO-1 (MW375) in cells expressing rat or human P2X(7) receptors. 4 There were, however, species differences in agonist potency such that 100 mu M BzATP was a supra-maximal concentration at rat, but not human or mouse, P2X(7) receptors. Importantly, when sub-maximal concentrations of BzATP or ATP were examined, current growth occurred at rat P2X(7) receptors. 5 The rate of current growth and YO-PRO-1 accumulation increased with agonist concentration and appeared more rapid at rat and human, than at mouse P2X(7) receptors. 6 The potency of BzATP and ATP was 1.5-10 fold lower in naive cells than in cells repeatedly exposed to ATP. 7 This study demonstrates that current growth occurs at mouse, rat and human P2X(7) receptors but only when using sub-maximal concentrations of agonist. Previously, current growth was thought to reflect the progressive increase in pore diameter of the P2X(7) receptor ion channel, however, the results of this study suggest a progressive increase in agonist potency may also contribute.