Gamma-aminobutyric acid (GABA): a para- and/or autocrine hormone in the pituitary

Abstract

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the brain. Furthermore, by acting through pituitary GABA A -, GABA B -, and GABA C receptors, it also plays an important role in the regulation of pituitary function. Although it has generally been assumed that the source of this pituitary GABA is the hypothalamus, here we provide evidence that GABA synthesis also occurs within the pituitary gland itself. Using RT-PCR, in situ hybridization histochemistry, immunohistochemistry, and immunoelectron microscopy, were detected the GABA synthesizing enzyme glutamic acid decarboxylase (GAD 67), the vesicular GABA transporter (VIAAT/VGAT), and GABA in the rat and rhesus monkey pituitary. Although these proteins were found in all of the endocrine cells of the intermediate lobe, we found these proteins in the growth hormone (GH) producing endocrine cells in the anterior lobe only, as well as in a rat GH producing cell line (GH3). In addition, GAD enzyme activity was readily detectable in the rat pituitary and GH3 cells. Many endocrine cells in the anterior pituitary, including GH-cells as well as PRL-, TSH-, ACTH-, and LH/FSH-cells were found to contain GABA A and or GABA B receptors, as shown by double-immunofluorescence staining. Therefore the identification of a novel site of synthesis of GABA within the pituitary, namely POMC-cells of the intermediate lobe and GH cells in the anterior lobe and the presence of pituitary GABA receptors, imply unexpected auto/paracrine actions of the neurotransmitter GABA to occur within the pituitary. These results suggest a new basic mechanism in the regulation of pituitary function by GABA.

Molecular and Physiological Evidence for Functional γ-Aminobutyric Acid (GABA)-C Receptors in Growth Hormone-secreting Cells

“…The opening of GABA-C channels may induce a membrane depolarization as suggested by an increase in Ca 2ϩ i levels measured by fluorometry on GH3 cells. In the pituitary gland, all types of GABA receptors are expressed (7,8,17), and GABA, produced either by the hypothalamus or by the pituitary itself (7,18,19), is known to be involved in the regulation of hormone levels (8,20,21). Interestingly GABA-C receptors were demonstrated previously in pituitary TSH cells (6).…”

“…Most likely, variations in the subunit composition (29), species-dependent protein sequence differences, or/and tissue-specific splicing variants (6) account for these different properties. In addition, we reported previously the presence of the GABA-A receptor subunit ␥ 2 in rat GH cells (7). The possibility that heterooligomerization might occur among and GABA-A subunits is under debate (30,31) and may also explain various electrogenic profiles.…”

“…They were painlessly killed under ether anesthesia, according to institutional animal care guidelines. The tissues were removed and processed as described previously (7,8).…”

“…In addition, functional GABA-C receptors were also observed in pituitary thyroid-stimulating hormone (TSH) cells using electrophysiological techniques (6). GABA, produced by growth hormone-(GH) secreting cells (7), acts as an autocrine regulator of GH levels via GABA-B receptors (8). In the present study, we report that GH cells also express GABA-C receptor subunits, which form functional receptors in a rat GH-producing cell line, GH3.…”

Gaba Uptake by Gat1 Modulates Long-Term Optical Changes Following Electrical Stimulation of the Pituitary Gland Neurointermediate Lobe

“…In addition, GABAergic hypothalamic neurons, which also project their axons through the infundibular stalk, terminate at the border between the neurohypophysis and the pars intermedia, where they make contact with pars intermedia cells. 1,2 In this way, GABA, secreted in response to infundibular stalk stimulation, is capable of modulating activity in the pars intermedia.…”