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J. Biol. Chem., Vol. 281, Issue 25, 17228-17237, June 23, 2006

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A Truncated P2X₇ Receptor Variant (P2X_7-j) Endogenously Expressed in Cervical Cancer Cells Antagonizes the Full-length P2X₇ Receptor through Hetero-oligomerization^*

Ying-Hong Feng¹, Xin Li¹, Liqin Wang, Lingying Zhou, and George I. Gorodeski^¶||2

From the Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814 and the Departments of Reproductive Biology, ^¶Physiology and Biophysics, and ^||Oncology, Case Western Reserve University, Cleveland, Ohio 44106

A truncated naturally occurring variant of the human receptor P2X₇ was identified in cancer cervical cells. The novel protein (P2X_7-j), a polypeptide of 258 amino acids, lacks the entire intracellular carboxyl terminus, the second transmembrane domain, and the distal third of the extracellular loop of the full-length P2X₇ receptor. The P2X_7-j was expressed in the plasma membrane; it showed diminished ligand-binding and channel function capacities and failed to form pores and mediate apoptosis in response to treatment with the P2X₇ receptor agonist benzoyl-ATP. The P2X_7-j interacted with the full-length P2X₇ in a manner suggesting heterooligomerization and blocked the P2X₇-mediated actions. Interestingly, P2X_7-j immunoreactivity and mRNA expression were similar in lysates of human cancer and normal cervical tissues, but fulllength P2X₇ immunoreactivity and mRNA expression were higher in normal than in cancer tissues, and cancer tissues lacked 205-kDa P2X₇ immunoreactivity suggesting lack of P2X₇ homo(tri)-oligomerization. These results identify a novel P2X₇ variant with apoptosis-inhibitory actions, and demonstrate a distinct regulatory property for a truncated variant to antagonize its full-length counterpart through hetero-oligomerization. This may represent a general paradigm for regulation of a protein function by its variant.

Received for publication, March 29, 2006 , and in revised form, April 18, 2006.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ399293 [GenBank] .

^* The work was supported in part by American Heart Association Scientist Development Grant 0030019N and NHLBI National Institutes of Health Grants HL65492 (to Y.-H. F.) and HD29924 and AG15955 (to G. I. G.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: University MacDonald Women's Hospital, University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, OH 44106. Tel.: 216-844-5977; Fax: 216-983-0091; E-mail: gig{at}cwru.edu.

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