Vasopressin and other neuropeptides are believed to serve as autocrine growth factors for small-cell carcinoma of the lung (SCCL), and these mitogenic influences are reported to involve increases in intracellular Ca2+. Of the classical and variant forms of SCCL, the latter is not only more drug-resistant but also refractory to vasopressin, and other peptides, with respect to changes in intracellular Ca2+. It is currently unclear if this refractiveness of variant SCCL is due to the absence of involved peptide receptors, to the production of abnormal receptors, or to abnormalities in components of induced transduction cascades. In this study, the presence of structurally-normal and functional vasopressin V1a receptors, was examined in a classical SCCL cell line (NCI H345) that is Ca(2+)-responsive to vasopressin, and a variant SCCL cell line (NCI H82) that is unresponsive in this regard to the peptide. Both cell lines were shown to express an mRNA of 1.9 Kb for the vasopressin V1a receptor. RT-PCR, cloning, and DNA sequencing revealed the structure of the mRNA was identical for both cell lines, and, in turn, identical to the mRNA expressed for this receptor by human liver cells. In both cell lines and liver, this mRNA was shown by Western analysis and RIA to generate major protein products of approximately 70,000 and 43,000 daltons. Vasopressin action on NCI H82 cells resulted in a substantial rise in the levels of total inositol phosphates. However, it was reaffirmed that these changes in inositol phosphates were not accompanied by a rise in Ca2+ levels. All of these data indicate that variant SCCL, as well as classical SCCL, expresses structurally-normal and functional vasopressin V1a receptors, but their activation in variant SCCL raises IP3 levels without a corresponding rise in intracellular Ca2+. This difference between the two SCCL sub-types therefore involves either steps in the inositol triphosphate cascade beyond the activation of phospholipase C, or alternatively, components of other transduction events that might be involved with changes in intracellular Ca2+.