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Vol. 56, Issue 5, 973-981, November 1999
Geneva Biomedical Research Institute, Glaxo Wellcome Research and
Development, Geneva, Switzerland
P2X receptors are membrane proteins that incorporate a cation-selective
ion channel that can be opened by the binding of extracellular ATP.
They associate as hetero- and homo-multimers of currently unknown
stoichiometry. In this study, we have used Xenopus
laevis oocytes to express rat P2X2 receptor
subunits, which carry a cysteine mutation at position 336. ATP-induced
currents at this mutant receptor subunit were blocked by more than 90%
when exposed to [2-(trimethylammonium) ethyl] methanethiosulfonate
(MTSET), whereas currents from wild-type subunits were not affected. To
compare mutant and wild-type channel expression, we introduced an
epitope in their extracellular domains and found for both channels a
similar linear relationship between antibody binding and currents
induced by ATP. To study the contribution of the individual subunits to the block by MTSET, we coinjected different mixtures of wild-type and
mutant-encoding mRNAs. We found that the inhibition by MTSET depended
linearly on the proportion of mutant subunits, which was clearly
contrary to the hypothesis that a single mutant subunit could act in a
dominant fashion. Subsequent concatenation of wild-type and
mutant-encoding cDNAs resulted in an inhibition by MTSET that also
depended linearly on the number of mutant subunits and was independent
of the position of the mutant subunit, as long as only two or three
P2X2 subunits were joined. With four or six subunits
joined, however, the inhibition by MTSET became strongly position-dependent. The present results show that a "per-subunit" channel block causes the blocking effects of MTSET and they suggest that not four but maximally three subunits actively participate in the
channel formation.
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