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

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 ntitogenic influences through the Vasopressin V,., receptor, and we have previously demon strated that this receptor is expressed by classical and variant SCCL. Activation of the vasopressin Vla receptor produces changes in phospholipases C, D, and \2, in protein kinase C, and in Qr* mobilization. This study demonstrates that SCCL cells express not only vasopressin V,., receptors but also iiiRNAs and proteins representing normal Vlb recep tors and V2 receptors. They were also shown to express mRNA for a human form of the putative receptor rabbit vasopressin-activated calci um-mobilizing receptor (VACM-1). Additionally, SCCL tumor cells were found to express mRNA and protein representing a possible nonfunc tional, shortened, "diabetic" form of the vasopressin V., 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 V, receptors between classical and variant SCCL were found. How ever, although the nature and expression of both vasopressin V, receptors and human VACM are apparently unaffected by dedifferentiation in SCCL, only the abnormal (and probably nonfunctional) form of the V, receptor could be demonstrated in variant cell line NCI H82. Functional engagement of vasopressin V, receptors is reported to produce rises in cAMP and activation of protein kinase A, whereas stimulation of V,b receptors is believed to produce similar changes to those produced by VIa receptors, i.e., activation of phospholipases and of protein kinase C. Stimulation of VACM receptors raises intracellular free C'ir ' 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.