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      Effect of Androgens on Sexual Differentiation of Pituitary Gamma-Aminobutyric Acid Receptor Subunit GABA B Expression

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          Previous work demonstrated a sexually dimorphic ontogenic expression of γ-aminobutyric acid receptors (GABA<sub>B</sub>R) in rat pituitary. As sex steroids determine sex-specific expression patterns, we now studied the effect of sex hormones on pituitary GABA<sub>B</sub>R expression. GABA<sub>B</sub>R subunits, measured by Western blot and by semi-quantitative RT-PCR and luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone measured by RIA were determined in two experimental designs: First experimental design: 8- and 15-day-old females (8F, 15F); 8F and 15F treated with 100 µg testosterone propionate (TP) on day 1 of life (8F100TP, 15F100TP), 8- and 15-day-old males (8M, 15M) and 8M and 15M castrated on day 1 (8MC, 15MC). Second experimental design: 8-day-old female and male animals: 8F, 8F100TP, 8F treated with 1 µg/day TP on days 1–4 (8F1TP), 8F treated with the androgen antagonist Flutamide (Flut: 2.5 mg/100 g BW of pregnant mother on days E17-E23) (8F-Flut), 8M, 8MC, 8M treated with Flut as above (8M-Flut) and 8MC-Flut. In these animals, in addition, GABA, glutamate, aspartate and taurine were measured by HPLC in hypothalami and cortex. In the first set of experiments, GABA<sub>B1</sub>R mRNA/protein expression was higher in 8F than in 15F, 8M or 15M. In 8F100TP, GABA<sub>B1</sub>R mRNA/protein decreased to male levels. TP treatment did not alter GABA<sub>B1</sub>R expression in 15F. There was no difference in GABA<sub>B1</sub>R expression between 8M and 15M and neonatal castration did not modify its expression. In the second set of experiments, TP (1 µg) or Flut did not modify GABA<sub>B1</sub>R in 8F, while 100 µg TP continued to decrease GABA<sub>B1</sub>R expression. In 8M, Flut, alone or with castration, increased GABA<sub>B1</sub>R mRNA/protein expression to 8F. Hypothalamic GABA content followed the same pattern as pituitary GABA<sub>B</sub>R expression in 8-day-old animals, suggesting a cross-regulation. With regard to hormonal levels, 100 µg, but not 1 µg TP altered gonadotropins at 8 days, although both treatments effectively androgenized females as evidenced by lack of cycling. We conclude that androgens, acting pre- and postnatally, decrease pituitary GABA<sub>B</sub>R subunit expression.

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          Most cited references 57

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          Heterodimerization is required for the formation of a functional GABA(B) receptor.

          GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. The gene encoding a GABA(B) receptor (GABA(B)R1) has been cloned; however, when expressed in mammalian cells this receptor is retained as an immature glycoprotein on intracellular membranes and exhibits low affinity for agonists compared with the endogenous receptor on brain membranes. Here we report the cloning of a complementary DNA encoding a new subtype of the GABAB receptor (GABA(B)R2), which we identified by mining expressed-sequence-tag databases. Yeast two-hybrid screening showed that this new GABA(B)R2-receptor subtype forms heterodimers with GABA(B)R1 through an interaction at their intracellular carboxy-terminal tails. Upon expression with GABA(B)R2 in HEK293T cells, GABA(B)R1 is terminally glycosylated and expressed at the cell surface. Co-expression of the two receptors produces a fully functional GABA(B) receptor at the cell surface; this receptor binds GABA with a high affinity equivalent to that of the endogenous brain receptor. These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2.
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            GABA(B)-receptor subtypes assemble into functional heteromeric complexes.

            B-type receptors for the neurotransmitter GABA (gamma-aminobutyric acid) inhibit neuronal activity through G-protein-coupled second-messenger systems, which regulate the release of neurotransmitters and the activity of ion channels and adenylyl cyclase. Physiological and biochemical studies show that there are differences in drug efficiencies at different GABA(B) receptors, so it is expected that GABA(B)-receptor (GABA(B)R) subtypes exist. Two GABA(B)-receptor splice variants have been cloned (GABA(B)R1a and GABA(B)R1b), but native GABA(B) receptors and recombinant receptors showed unexplained differences in agonist-binding potencies. Moreover, the activation of presumed effector ion channels in heterologous cells expressing the recombinant receptors proved difficult. Here we describe a new GABA(B) receptor subtype, GABA(B)R2, which does not bind available GABA(B) antagonists with measurable potency. GABA(B)R1a, GABA(B)R1b and GABA(B)R2 alone do not activate Kir3-type potassium channels efficiently, but co-expression of these receptors yields a robust coupling to activation of Kir3 channels. We provide evidence for the assembly of heteromeric GABA(B) receptors in vivo and show that GABA(B)R2 and GABA(B)R1a/b proteins immunoprecipitate and localize together at dendritic spines. The heteromeric receptor complexes exhibit a significant increase in agonist- and partial-agonist-binding potencies as compared with individual receptors and probably represent the predominant native GABA(B) receptor. Heteromeric assembly among G-protein-coupled receptors has not, to our knowledge, been described before.
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              Gonadal steroid induction of structural sex differences in the central nervous system.

               R Gorski,  A. Arnold (1983)

                Author and article information

                S. Karger AG
                January 2005
                18 January 2005
                : 80
                : 3
                : 129-142
                aInstituto de Biología y Medicina Experimental-CONICET, and bDepartment of Physiology, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina; cDepartment of Clinical-Biological Sciences, Biozentrum/Pharmazentrum, University of Basel, Basel, Switzerland
                82527 Neuroendocrinology 2004;80:129–142
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 11, Tables: 1, References: 74, Pages: 14
                Gonadal Steroid Feedback and Gonadotropins


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