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J Biol Chem, Vol. 274, Issue 40, 28682-28689, October 1, 1999

The Proximal Portion of the COOH Terminus of the Oxytocin Receptor Is Required for Coupling to G_q, but Not G_i
INDEPENDENT MECHANISMS FOR ELEVATING INTRACELLULAR CALCIUM CONCENTRATIONS FROM INTRACELLULAR STORES

Sarasija Hoare, John A. Copland, Zuzana Strakova, Kirk Ives^§, Yow-Jiun Jeng, Mark R. Hellmich^§, and Melvyn S. Soloff^¶

From the Departments of  Obstetrics and Gynecology, ^§ Surgery, and the ^¶ Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, Texas 77555-1062

As the oxytocin receptor plays a key role in parturition and lactation, there is considerable interest in defining its structure/functional relationships. We previously showed that the rat oxytocin receptor transfected into Chinese hamster ovary cells was coupled to both G_q/11 and G_i/o, and that oxytocin stimulated ERK-2 phosphorylation and prostaglandin E₂ synthesis via protein kinase C activity. In this study, we show that deletion of 51 amino acid residues from the carboxyl terminus resulted in reduced affinity for oxytocin and a corresponding rightward shift in the dose-response curve for oxytocin-stimulated [Ca²⁺]_i. However, oxytocin-stimulated ERK-2 phosphorylation and prostaglandin E₂ synthesis did not occur in cells expressing the truncated receptor. Oxytocin also failed to increase phospholipase A activity or activate protein kinase C, indicating that the mutant receptor is uncoupled from G_q-mediated pathways. The 51 receptor is coupled to G_i, as oxytocin-stimulated Ca²⁺ transients were inhibited by pertussis toxin, and a G sequestrant. Preincubation of 51 cells with the tyrosine kinase inhibitor, genistein, also blocked the oxytocin effect. A 39 mutant had all the activities of the wild type oxytocin receptor. These results show that the portion between 39 and 51 residues from the COOH terminus of the rat oxytocin receptor is required for interaction with G_q/11, but not G_i/o. Furthermore, an increase in intracellular calcium was generated via a G_i-tyrosine kinase pathway from intracellular stores that are distinct from G_q-mediated inositol trisphosphate-regulated stores.

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