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The Human V₃ Pituitary Vasopressin Receptor: Ligand Binding Profile and Density-Dependent Signaling Pathways¹

Departments of Medicine and Physiology, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio 44106-4951

Address all correspondence and requests for reprints to: Dr. Marc Thibonnier, Room BRB431, Division of Clinical and Molecular Endocrinology, Department of Medicine, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106-4951. E-mail: mxt10{at}po.cwru.edu

The vasopressin (AVP) V₃ pituitary receptor (V₃R) is a G protein-coupled corticotropic phenotypic marker that is overexpressed in ACTH-hypersecreting tumors. Studies of the agonist/antagonist binding profile and signal transduction pathways linked to the human V₃R have been limited because of the scarcity of this protein. To define the signals activated by V₃Rs and the eventual changes triggered by developmental or pathological receptor regulation, we developed Chinese hamster ovary (CHO)-V₃ cells stably expressing low, medium, or high levels of human V₃Rs (binding capacity, <10, 10–25, and 25–100 pmol/mg, respectively).

The affinity of the V₃R for 21 peptide and nonpeptide AVP analogs was clearly distinct from that exhibited by the human V₁R and V₂R. AVP triggered stimulation of phospholipase C in CHO-V₃ cells (partially sensitive to treatment with pertussis toxin) with a potency directly proportional to receptor density. V₃R-mediated arachidonic acid release also was also sensitive to pertussis toxin and more efficacious in cells exhibiting medium than in those with high receptor density. AVP also stimulated the pertussis toxin-insensitive uptake of [³H]thymidine in CHO-V₃ cells. The concentration-response curves for this effect were monophasic in cells expressing low and medium levels of V₃Rs; on the contrary, a biphasic curve was observed in cells with high V₃R density. Coupling of V₃R to increased production of cAMP was only observed in CHOV₃ high cells, suggesting a negative relationship between increased cAMP production and DNA synthesis. Activation of mitogen-activated protein kinases by V₃R was pertussis toxin insensitive, but was dependent on activation of phospholipase C and protein kinase C; both the level and duration of activation were a function of the receptor density.

Thus, the human V₃R has a pharmacological profile clearly distinct from that of the human V₁R and V₂R and activates several signaling pathways via different G proteins, depending on the level of receptor expression. The increased synthesis of DNA and cAMP levels observed in cells expressing medium and high levels of V₃Rs, respectively, may represent important events in the tumorigenesis of corticotroph cells.

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