We have previously shown that some of human growth hormone (GH)-producing pituitary adenomas preferentially express a larger transcript of GH-releasing hormone (GHRH) receptor (GHRH-R). This transcriptional variant is presumed to be produced by alternative messenger RNA splicing and contains premature stop codon in frame, predicted to yield a truncated GHRH-R. Functional expression study indicated that the variant receptor was unable to transduct GHRH signals. To determine the functional relationship between the splice-variant and the wild-type GHRH-R, the expression vector for the variant GHRH-R transcript was transfected into COS-7 cells together with or without that for the wild GHRH-R transcript. In cells transfected with both GHRH-R expression vectors, GHRH-dependent cyclic adenosine monophosphate (cAMP) induction was decreased to 39% of that in the cells transfected with the wild-type GHRH-R expression vector alone. This inhibition was found to be irrespective of the concentration (10(-8) to 10(-5) mol/L) of GHRH. These findings suggest that the splice variant form of GHRH-R functions as a dominant-negative modulator in GHRH-induced cellular signaling.