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Address correspondence to Baljit S. Khakh, Division of Neurobiology, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. Fax (44) 1223-402310; E-mail: bsk{at}mrc-lmb.cam.ac.uk; or Henry A. Lester, Division of Biology 156-29, California Institute of Technology, 1201 East California Boulevard, Pasadena, CA 91125-2900. Fax: (626) 564-8709; E-mail: lester{at}caltech.edu
ATP-gated P2X channels are the simplest of the three families of transmitter-gated ion channels. Some P2X channels display a time- and activation-dependent change in permeability as they undergo the transition from the relatively Na+-selective I1 state to the I2 state, which is also permeable to organic cations. We report that the previously reported permeability change of rat P2X2 (rP2X2) channels does not occur at mouse P2X2 (mP2X2) channels expressed in oocytes. Domain swaps, species chimeras, and point mutations were employed to determine that two specific amino acid residues in the cytosolic tail domain govern this difference in behavior between the two orthologous channels. The change in pore diameter was characterized using reversal potential measurements and excluded field theory for several organic ions; both rP2X2 and mP2X2 channels have a pore diameter of 
11 Å in the I1 state, but the transition to the I2 state increases the rP2X2 diameter by at least 3 Å. The I1 to I2 transition occurs with a rate constant of 0.5 s-1. The data focus attention on specific residues of P2X2 channel cytoplasmic domains as determinants of permeation in a state-specific manner.
Key Words: ATP • ion channel • modulation • P2X • purinoceptor
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