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¹ Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
² Instituto de Química Física de los Materiales, Medio Ambiente y Energía, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, 1428, Argentina

Correspondence to Luciano Moffatt: lmoffatt{at}qi.fcen.uba.ar

To gain insight into the way that P2X₂ receptors localized at synapses might function, we explored the properties of outside-out patches containing many of these channels as ATP was very rapidly applied and removed. Using a new method to calibrate the speed of exchange of solution over intact patches, we were able to reliably produce applications of ATP lasting <200 µs. For all concentrations of ATP, there was a delay of at least 80 µs between the time when ATP arrived at the receptor and the first detectable flow of inward current. In response to 200-µs pulses of ATP, the time constant of the rising phase of the current was 600 µs. Thus, most channel openings occurred when no free ATP was present. The current deactivated with a time constant of 60 ms. The amplitude of the peak response to a brief pulse of a saturating concentration of ATP was 70% of that obtained during a long application of the same concentration of ATP. Thus, ATP leaves fully liganded channels without producing an opening at least 30% of the time. Extensive kinetic modeling revealed three different schemes that fit the data well, a sequential model and two allosteric models. To account for the delay in opening at saturating ATP, it was necessary to incorporate an intermediate closed state into all three schemes. These kinetic properties indicate that responses to ATP at synapses that use homomeric P2X₂ receptors would be expected to greatly outlast the duration of the synaptic ATP transient produced by a single presynaptic spike. Like NMDA receptors, P2X₂ receptors provide the potential for complex patterns of synaptic integration over a time scale of hundreds of milliseconds.

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