Receptors and sites of synthesis and storage of gamma-aminobutyric acid in human pituitary glands and in growth hormone adenomas.

gamma-Aminobutyric acid (GABA) is an important regulatory factor of pituitary gland function, which, in addition to hypothalamic neurons, can be derived from intrapituitary sources, ie, growth hormone (GH) cells of rat and monkey. We report that human pituitary glands also express 2 isoforms of the GABA-synthesizing enzyme glutamate decarboxylase (GAD 65; GAD 67), the vesicular GABA transporter (VGAT), and multiple subunits of GABA (A, B, and Q receptors. GABA production and storage occurs in GH cells, as demonstrated by cellular colocalization of immunoreactive GAD and VGAT in GH cells and by reverse transcription-polymerase chain reaction analysis of laser capture-microdissected immunostained GH cells. It is interesting that human pituitary GH adenomas share expression of VGAT and GABA receptors with normal pituitary glands but lack GAD 65. We propose that GABA, synthesized by GH cells, might act as a paracrine or autocrine regulating factor in the human pituitary gland and in human GH adenoma. Because many drugs interfere with GABA function, the identification of GABA system components might have clinical implications. gamma-Aminobutyric acid (GABA) is the prevailing inhibitory neurotransmitter in the mammalian central nervous system, but it also is an important regulatory factor of several endocrine tissues and organs. It is clear that GABA can be synthesized and released from endocrine cells to influence neighboring cells in a local, paracrine manner. The endocrine GABA-producing cells are characterized by the expression of GABA-synthesizing enzymes and the vesicular GABA transporter (VGAT), whereas the target cells express ionotropic GABA-A and GABA-C receptors and/or metabotropic GABA-B receptors. These interactions are best established in the pancreatic islet. There, GABA is synthesized via glutamate decarboxylase (GAD), cosecreted with insulin from P cells, and influences a cells via GABA-A receptors. Although the physiologic significance of this GABA effect to the regulation of blood glucose levels is unknown, it has a clinical implication. Autoantibodies that recognize GAD in pancreatic islets are involved in the pathogenesis of type 1 diabetes mellitus. Recently, less well-studied endocrine organs have been recognized to synthesize GABA and to have GABA receptors. They include the adrenal cortex, Leydig cells of the testicular interstitium, and, in particular, the pituitary. GABA affecting pituitary gland function is derived from the hypothalamus and from a novel, intrapituitary GABA source, recently described in rats and rhesus monkeys. This source comprises growth hormone (GH) cells of the anterior lobe and pro-opiomelanocortin cells of the intermediate lobe. In GH and pro-opiomelanocortin cells of these mammals, GAD 67, VGAT, and GABA are present. Furthermore, subunits of all classes of GABA receptors (A, B, and Q are expressed by the 5 different endocrine cell types of the anterior lobe.,14-16 It can be concluded from the presence of GABA receptors that GABA might act in a paracrine and/or autocrine manner in the pituitary gland. The knowledge of the cellular expression of GABA receptor subunits is sparse, but it has been shown that GABA-B receptor R subunits are expressed by GH-producing cells of the rat pituitary and by the GH3 cell line, in which they are involved in the control of GH synthesis and secretion. GABA-C receptor p subunits also were found in GH cells of the rat pituitary and in GH3 cells and are described to form functional chloride channels. Thus, locally produced GABA likely acts as a complementary regulator of pituitary function. The importance of GABAergie regulation is well documented in rodents. There, GABA specifically controls the secretion of the hormones corticotropin, GH, luteinizing hormone, prolactin, and thyroid-stimulating hormone. Because most studies focused on nonhuman species, nothing is known about a local, intrapituitary GABA system in humans. However, knowledge about its existence might be of clinical interest because not only are drugs interfering with GABA metabolism and GABA receptors in extensive clinical use, but also autoantibodies against GAD are associated with several diseases, eg, type 1 diabetes mellitus and the stiff-man syndrome. We studied whether human pituitary glands and GH adenomas possess the components necessary for a functional GABA system (ie, GAD 65 and GAD 67, VGAT, and GABA receptors). We especially focused on the question of whether human GH cells are the site of GABA synthesis.