Autoregulation of growth hormone receptor and growth hormone binding protein transcripts in brain and peripheral...

Growth hormone (GH) differs from other pituitary hormones in that it can affect a wide spectrum of cellular activities in many different tissues. These disparate actions are, however, mediated by a common receptor, suggesting tissue-specific differences in the post-receptor mechanisms and/or tissue sensitivities to GH stimulation may confer specificity. Tissue sensitivity depends upon the abundance of GH receptors (GHRs) and may be modulated by the amplitude and pulsatility of GH secretion. It may also be dependent upon the presence of non-signal transducing GH-binding proteins (GHBPs), which result from the alternate splicing of GHR gene transcripts. Tissue-specific autoregulation of GHRs and GHBPs could, therefore, contribute to differential tissue responsiveness to GH action. The autoregulation of GHR and GHBP gene transcription in novel central (hypothalamus, brainstem, and cortex/neocortex) and peripheral (spleen) tissues was therefore examined in adult, male Sprague-Dawley rats. For comparative purposes, GHR/GHBP gene expression was also examined in the liver, which has traditionally been considered the major GH-target site. Chronic hyposomatotropism, induced by hypophysectomy, exerted tissue-specific effects on the abundance of GHR gene products 10 days post-hypophysectomy. Both GHR and GHBP transcripts were reduced in the hypothalamus of hypophysectomized rats by 20% (P < 0.001), although neither transcript was affected in the liver, spleen, cortex/neocortex or brainstem. In contrast, 2 h after a single bolus GH injection that was designed to simulate a pulsatile increase in circulating GH concentrations, GHR and GHBP mRNA content was significantly increased by 25-30% (P < 0.001) in all brain regions and in the spleen of hypophysectomized or sham-hypophysectomized rats. Production of the two transcripts was differentially regulated, however, as GHBP, but not GHR, transcripts were increased in the liver (P < 0.001), whereas the GHR:GHBP ratio was decreased in the hypothalamus of GH-treated rats (P < 0.001). These results suggest that GHR gene transcription and splicing are acutely autoregulated in a tissue-specific way.