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Expression of All Known Vasopressin Receptor Subtypes by Small Cell Tumors Implies a Multifaceted Role for this Neuropeptide¹

Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire 03756

Vasopressin is one of several small neuropeptides that are reported to be autocrine growth factors for small cell carcinoma of the lung (SCCL). It has been assumed that this peptide exercises its mitogenic influences through the vasopressin V_1a receptor, and we have previously demonstrated that this receptor is expressed by classical and variant SCCL. Activation of the vasopressin V_1a receptor produces changes in phospholipases C, D, and A₂, in protein kinase C, and in Ca²⁺ mobilization. This study demonstrates that SCCL cells express not only vasopressin V_1a receptors but also mRNAs and proteins representing normal V_1b receptors and V₂ receptors. They were also shown to express mRNA for a human form of the putative receptor rabbit vasopressin-activated calcium-mobilizing receptor (VACM-1). Additionally, SCCL tumor cells were found to express mRNA and protein representing a possible nonfunctional, shortened, "diabetic" form of the vasopressin V₂ receptor that is the product of incomplete posttranscriptional splicing. At least four of these five vasopressin receptors were produced by cell lines exemplifying classical and variant forms of SCCL. No differences in the sequences for the V₁ receptors between classical and variant SCCL were found. However, although the nature and expression of both vasopressin V₁ receptors and human VACM are apparently unaffected by dedifferentiation in SCCL, only the abnormal (and probably nonfunctional) form of the V₂ receptor could be demonstrated in variant cell line NCI H82. Functional engagement of vasopressin V₂ receptors is reported to produce rises in cAMP and activation of protein kinase A, whereas stimulation of V_1b receptors is believed to produce similar changes to those produced by V_1a receptors, i.e., activation of phospholipases and of protein kinase C. Stimulation of VACM receptors raises intracellular free Ca²⁺ through currently unknown but phosphoinositide-independent mechanisms. The presence of all known vasopressin receptors that are, together, potentially capable of inducing several different transduction cascades in small cell tumor cells suggests that this peptide serves a multifaceted role in tumor physiology.

¹ This work was supported in part by United States Public Health Service Award CA 19613. M. J. F. was supported as a postdoctoral fellow on NIH Training Grant T32 DK 07508, and K. A. L. was supported by fellowships from the Dolores Zhorhab Liebmann Foundation and the Stephen J. Ryan Foundation.

² To whom requests for reprints should be addressed, at Department of Physiology, Dartmouth Medical School, Borwell 752E, 1 Medical Center Drive, Lebanon, NH 03756.

³ Present address: Department of Pharmacology, MidWestern University, Downers Grove, IL 60515.

Received 11/25/97. Accepted 3/ 4/98.

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