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J. Biol. Chem., Vol. 281, Issue 22, 15044-15049, June 2, 2006

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A C-terminal Lysine That Controls Human P2X₄ Receptor Desensitization^*

From the Faculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester, M13 9PT, United Kingdom

Receptor desensitization can determine the time course of transmitter action and profoundly alter sensitivity to drugs. Among P2X receptors, ion currents through homomeric P2X₄ receptors exhibit intermediate desensitization when compared with P2X₁ and P2X₃ (much faster) and P2X₂ and P2X₇ (slower). We recorded membrane currents in HEK293 cells transfected to express the human P2X₄ receptor. The decline in current during a 4-s application of ATP (100 µM) was about 30%; this was not different during whole-cell or perforated patch recording. Alanine-scanning mutagenesis of the intracellular C terminus identified two positions with much accelerated desensitization kinetics (Lys³⁷³: 92% and Tyr³⁷⁴: 74%). At position 373, substitution of Arg or Cys also strongly accelerated desensitization: however, in the case of K373C the wild-type phenotype was fully restored by adding ethylammonium methanethiosulfonate. At position 374, phenylalanine could replace tyrosine. These results indicate that wild-type desensitization properties requires an aromatic moiety at position 374 and an amino rather than a guanidino group at position 373. These residues lie between previously identified motifs involved in membrane trafficking (YXXXK and YXXGL) and implicates the C-terminal also in rearrangements leading to channel closing during the presence of agonist.

Received for publication, January 17, 2006 , and in revised form, March 6, 2006.

^* This work was supported by The Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. E-mail: Samuel.fountain{at}manchester.ac.uk.

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