INHIBITION OF SIGNAL-TRANSDUCTION BY A SPLICE VARIANT OF THE GROWTH HORMONE-RELEASING HORMONE-RECEPTOR EXPRESSED IN HUMAN PITUITARY-ADENOMAS

We have previously shown that some of human growth hormone (GH)-produc ing pituitary adenomas preferentially express a larger transcript of G H-releasing hormone (GMRH) receptor (GHRH-R). This transcriptional var iant is presumed to be produced by alternative messenger RNA splicing and contains premature stop codon in frame, predicted to yield a trunc ated GHRH-R. Functional expression study indicated that the variant re ceptor was unable to transduct GHRH signals. To determine the function al relationship between the splice-variant and the wild-type GHRH-R, t he expression vector for the variant GHRH-R transcript was transfected into COS-7 cells together with or without that for the wild GHRH-R tr anscript. In cells transfected with both GHRH-R expression vectors, GH RH-dependent cyclic: adenosine monophosphate (cAMP) induction was decr eased to 39% of that in the cells transfected with the wild-type GHRH- R expression vector alone. This inhibition was found to be irrespectiv e of the concentration (10(-8) to 10(-5) mol/L) of GHRH. These finding s suggest that the splice variant form of GHRH-W functions as a domina nt-negative modulator in GHRH-induced cellular signaling. Copyright (C ) 1998 by W.B. Saunders Company.