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An Intrinsic -Aminobutyric Acid (GABA)ergic System in the Adrenal Cortex: Findings from Human and Rat Adrenal Glands and the NCI-H295R Cell Line

Anatomisches Institut, Universität München, 80802 München, Germany

Address all correspondence and requests for reprints to: Dr. Manfred Gratzl, Anatomisches Institut der Universität München, Biedersteiner Strasse 29, 80802 München, Germany. E-mail: gratzl{at}LMU.de.

-Aminobutyric acid (GABA), a major neurotransmitter in the central nervous system, also acts as a paracrine or autocrine signaling molecule in endocrine tissues such as the pancreatic islets, adenohypophysis, and testis. In the present study, we describe local GABA production and functional GABA_B receptors in the adrenal cortex, possibly forming an auto- or paracrine GABAergic system. Using immunohistochemistry and RT-PCR, we localized the GABA-synthesizing enzyme glutamate decarboxylase 67 and the vesicular GABA transporter in steroid-producing cells of the human and rat adrenal cortex. Immunocytochemistry, Western blots, and RT-PCR experiments demonstrated the presence of glutamate decarboxylase 67 in the human adrenocortical cell line NCI-H295R. Measurements of glutamate decarboxylase activity confirmed that, in these cells and in rat adrenals, glutamate is decarboxylated to form GABA. In addition, we found expression of the GABA_B(1a), GABA_B(1e), and GABA_B(2) subunits of the heterodimeric GABA_B receptor in NCI-H295R cells as shown by RT-PCR. GABA_B(1a) and its truncated splice variant GABA_B(1e) were also found in human and rat adrenal glands. Immunostaining for the GABA_B(2) subunit revealed its presence in the human and rat adrenal cortex and in NCI-H295R cells. The GABA_B receptors we identified were functional because the GABA_B agonist baclofen inhibited T-type Ca²⁺ currents in whole-cell patch clamp experiments on NCI-H295R cells. This effect was blocked by pertussis toxin. Furthermore, the ₂-, ₃-, ß₂-, ß₃- ₂-, and -subunits of the GABA_A receptor were detected in this cell line by RT-PCR. Hence, we conclude that GABA is synthesized and stored by steroid-producing cells of the adrenal cortex and may influence these cells in a paracrine or autocrine manner.

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