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J. Biol. Chem., Vol. 279, Issue 45, 47017-47023, November 5, 2004

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Novel Down-regulatory Mechanism of the Surface Expression of the Vasopressin V₂ Receptor by an Alternative Splice Receptor Variant^*

José M. Sarmiento, Carolina C. Añazco, Danae M. Campos, Gregory N. Prado¶, Javier Navarro¶, and Carlos B. González||

From the Department of Physiology, Universidad Austral de Chile, Valdivia 2-5119300, Chile and the ^¶Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-0437

In rat kidney, two alternatively spliced transcripts are generated from the V₂ vasopressin receptor gene. The large transcript (1.2 kb) encodes the canonical V₂ receptor, whereas the small transcript encodes a splice variant displaying a distinct sequence corresponding to the putative seventh transmembrane domain and the intracellular C terminus of the V₂ receptor. This work showed that the small spliced transcript is translated in the rat kidney collecting tubules. However, the protein encoded by the small transcript (here called the V_2b splice variant) is retained inside the cell, in contrast to the preferential surface distribution of the V₂ receptor (here called the V_2a receptor). Cells expressing the V_2b splice variant do not exhibit binding to ³H-labeled vasopressin. Interestingly, we found that expression of the splice variant V_2b down-regulates the surface expression of the V_2a receptor, most likely via the formation of V_2a·V_2b heterodimers as demonstrated by co-immunoprecipitation and fluorescence resonance energy transfer experiments between the V_2a receptor and the V_2b splice variant. The V_2b splice variant would then be acting as a dominant negative. The effect of the V_2b splice variant is specific, as it does not affect the surface expression of the G protein-coupled interleukin-8 receptor (CXCR1). Furthermore, the sequence encompassing residues 242–339, corresponding to the C-terminal domain of the V_2b splice variant, also down-regulates the surface expression of the V_2a receptor. We suggest that some forms of nephrogenic diabetes insipidus are due to overexpression of the splice variant V_2b, which could retain the wild-type V_2a receptor inside the cell via the formation of V_2a·V_2b heterodimers.

Received for publication, August 31, 2004

^* This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) Grant 1030261 (to C. B. G.), Dirección de Investigación, Universidad Austral de Chile (DIDUACH) Grant 200204 (to J. M. S.), National Institutes of Health Grant R01 EY014218, and a grant from the Welch Foundation (to J. N.). 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.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed. Fax: 56-63-221513; E-mail: cbgonzal{at}uach.cl.

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