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      Insights into GABA Receptor Signalling in TM3 Leydig Cells

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          γ-Aminobutyric acid (GABA) is an emerging signalling molecule in endocrine organs, since it is produced by endocrine cells and acts via GABA<sub>A</sub> receptors in a paracrine/autocrine fashion. Testicular Leydig cells are producers and targets for GABA. These cells express GABA<sub>A</sub> receptor subunits and in the murine Leydig cell line TM3 pharmacological activation leads to increased proliferation. The signalling pathway of GABA in these cells is not known in this study. We therefore attempted to elucidate details of GABA<sub>A</sub> signalling in TM3 and adult mouse Leydig cells using several experimental approaches. TM3 cells not only express GABA<sub>A </sub>receptor subunits, but also bind the GABA agonist [<sup>3</sup>H]muscimol with a binding affinity in the range reported for other endocrine cells (K<sub>d</sub> = 2.740 ± 0.721 n M). However, they exhibit a low B<sub>max</sub> value of 28.08 fmol/mg protein. Typical GABA<sub>A</sub> receptor-associated events, including Cl<sup>–</sup> currents, changes in resting membrane potential, intracellular Ca<sup>2+</sup> or cAMP, were not measurable with the methods employed in TM3 cells, or, as studied in part, in primary mouse Leydig cells. GABA or GABA<sub>A</sub> agonist isoguvacine treatment resulted in increased or decreased levels of several mRNAs, including transcription factors (c-fos, hsf-1, egr-1) and cell cycle-associated genes (Cdk2, cyclin D1). In an attempt to verify the cDNA array results and because egr-1 was recently implied in Leydig cell development, we further studied this factor. RT-PCR and Western blotting confirmed a time-dependent regulation of egr-1 in TM3. In the postnatal testis egr-1 was seen in cytoplasmic and nuclear locations of developing Leydig cells, which bear GABA<sub>A</sub> receptors and correspond well to TM3 cells. Thus, GABA acts via an untypical novel signalling pathway in TM3 cells. Further details of this pathway remain to be elucidated.

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          Most cited references 47

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          Is there more to GABA than synaptic inhibition?

          In the mature brain, GABA (gamma-aminobutyric acid) functions primarily as an inhibitory neurotransmitter. But it can also act as a trophic factor during nervous system development to influence events such as proliferation, migration, differentiation, synapse maturation and cell death. GABA mediates these processes by the activation of traditional ionotropic and metabotropic receptors, and probably by both synaptic and non-synaptic mechanisms. However, the functional properties of GABA receptor signalling in the immature brain are significantly different from, and in some ways opposite to, those found in the adult brain. The unique features of the early-appearing GABA signalling systems might help to explain how GABA acts as a developmental signal.
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            Regulation of life and death by the zinc finger transcription factor Egr-1.

            The biosynthesis of the zinc finger transcription factor Egr-1 is stimulated by many extracellular signaling molecules including hormones, neurotransmitters, growth and differentiation factors, and cytotoxic metabolites. The 5'-flanking region of the Egr-1 gene contains genetic elements that are essential in connecting stimulation of the cells with enhanced transcription of the Egr-1 gene, and subsequently, transcription of Egr-1-responsive genes. Thus, Egr-1 links cellular signaling cascades with changes in the gene expression pattern. Many biological functions have been attributed to Egr-1. Here, we discuss evidence for Egr-1 control of cellular proliferation and programmed cell death. Copyright 2002 Wiley-Liss, Inc.
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              GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis.

              We have found that, during the early stages of cortical neurogenesis, both GABA and glutamate depolarize cells in the ventricular zone of rat embryonic neocortex. In the ventricular zone, glutamate acts on AMPA/kainate receptors, while GABA acts on GABAA receptors. GABA induces an inward current at resting membrane potentials, presumably owing to a high intracellular Cl- concentration maintained by furosemide-sensitive Cl- transport. GABA and glutamate also produce increases in intracellular Ca2+ in ventricular zone cells, in part through activation of voltage-gated Ca2+ channels. Furthermore, GABA and glutamate decrease the number of embryonic cortical cells synthesizing DNA. Depolarization with K+ similarly decreases DNA synthesis, suggesting that the neurotransmitters act via membrane depolarization. Applied alone, GABAA and AMPA/kainate receptor antagonists increase DNA synthesis, indicating that endogenously released amino acids influence neocortical progenitors in the cell cycle. These results demonstrate a novel role for amino acid neurotransmitters in regulating neocortical neurogenesis.

                Author and article information

                S. Karger AG
                November 2005
                30 November 2005
                : 81
                : 6
                : 381-390
                aAnatomisches Institut, Ludwig Maximilians University, Munich, Germany; bInstituto de Biologia y Medicina Experimental, Buenos Aires, Argentina; cInstitute of Anaesthesiology, University of Ulm, Ulm, Germany
                89556 Neuroendocrinology 2005;81:381–390
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 1, References: 66, Pages: 10
                Original Paper


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