Gamma-aminobutyric acid (GABA) in the human pituitary: Synthesis and storage in GH-cells of non-tumorous pituitary glands and in GH-adenomas

Abstract

Gamma-aminobutyric acid (GABA) is known as an important regulatory factor of pituitary gland function along the hypothalamic-hypophysial axis. We have recently shown that GABA is a para- and/or autocrine factor in the rat and rhesus monkey pituitary gland. GABA-action is exerted via GABA-A-, GABA-B- and GABA-C-receptors present in many endocrine cells of the anterior lobe. Furthermore GABA can be produced within the pituitary gland itself: Thus, GH-cells of the anterior lobe possess the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67), as well as the GABA-transporter (vesicular inhibitory aminoacid transporter VIAAT/vesicular GABA transporter VGAT). Whether GABA could also be synthesized in human GH-cells and act in the human pituitary gland is not known. We started to address this point by examining whether human pituitaries and human pituitary GH-adenomas express the GABA-synthesizing enzyme GAD, the vesicular GABA transporter VIAAT/VGAT and GABA-receptor-subunits. RT-PCR of non-tumorous pituitaries (n=5, 2 female, 3 male, 45–94 years old) and pituitary GH-adenomas (n=8, 2 female, 6 male, 18–51 years old) showed the presence of GAD, VIAAT, the β3- and γ2-subunit of the GABA-A-receptor, the R1-subunit of the GABA-B-receptor and the ρ2-subunit of the GABA-C-receptor. Immunohistochemical staining demonstrated GAD and VIAAT in GH-cells of non-tumorous pituitaries. In addition, cellular co-localisation of GH, GAD, VIAAT/VGAT was shown using consecutive sections of non-tumorous pituitaries which were immunostained sequentially. We also applied laser capture microdissection followed by RT-PCR to unequivocally identify GH-cells as the cell-type expressing GAD in non-tumorous pituitaries. In conclusion, these results show for the first time the existence of the enzyme for GABA-synthesis, its vesicular transporter and GABA-receptors in the human pituitary gland and in GH-adenomas. We propose that GABA – synthesized by GH-cells – may act as a para- and/or autocrine regulating factor not only in the rat and rhesus monkey but also in the human pituitary gland. (Supported by Eli Lilly International Foundation and Graduiertenkolleg 333)