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The Journal of Experimental Biology 206, 627-636 (2003)
doi: 10.1242/jeb.00105

PPNDS is an agonist, not an antagonist, for the ATP receptor of Paramecium

Christopher R. Wood and Todd M. Hennessey^*

Dept of Biological Sciences, State University of NY at Buffalo, Buffalo, NY 14260, USA

^* Author for correspondence (e-mail: thennes{at}acsu.buffalo.edu)

Accepted 28 October 2002

Paramecium represents a simple, eukaryotic model system to study the cellular effects of some neuroactive drugs. They respond to the agonist ß,-methylene ATP with a transient depolarizing receptor potential, Ca²⁺-based action potentials and repetitive bouts of forward and backward swimming called `avoiding reactions' (AR). In vivo [<sup>32</sup>P]ATP binding assays showed saturable [<sup>32</sup>P]ATP binding with an apparent K<sub>d</sub> of approximately 23 nmol l<sup>-1</sup>. Prolonged (15 min) exposure to 25 µmol l<sup>-1</sup> ß,-methylene ATP caused behavioral adaptation and losses of AR, ATP receptor potentials and [<sup>32</sup>P]ATP binding. While screening various ATP receptor inhibitors, we found that the P2X1 `antagonist' pyridoxal-phosphate naphthylazo-nitro-disulfate (PPNDS) is actually an agonist, producing the same responses as ß,-methylene ATP. [³²P]ATP binding assays suggest that both agonists may bind to the same site as [³²P]ATP. Cross-adaptation is also seen between PPNDS and ß,-methylene ATP in terms of losses in AR, depolarizing receptor potentials and [³²P]ATP binding. We conclude that the inhibition caused by PPNDS in Paramecium is due to agonist-induced desensitization. Either this represents a unique new class of ATP receptors, in which PPNDS is an agonist instead of an antagonist, or PPNDS (and other drugs like it) may actually be an agonist in many other cell types in which prolonged exposure is necessary for inhibition.

Key words: PPNDS, ATP receptor, P2X1 antagonist, adaptation, desensitization, Paramecium, ß,-methylene ATP