Inverse modulation of gamma-aminobutyric acid- and glycine-induced currents by progesterone

FS Wu, TT Gibbs and DH Farb

Department of Anatomy and Cell Biology, State University of New York, Health Science Center, Brooklyn 11203.

The ability of certain synthetic and endogenous steroids to modulate neuronal responses to gamma-aminobutyric acid (GABA) is well documented, but little is known of the effect of steroids on glycine responses. We show here that in voltage-clamped neurons progesterone (10-100 microM) itself enhances GABA-induced chloride currents but, surprisingly, antagonizes those induced by glycine. Some, but not all, progesterone metabolites also display these effects. The effects of progesterone on GABA and glycine responses are dose dependent, with EC50 values of 26 and 16 microM and maxima of +156 and -60%, respectively. Progesterone and its reduced metabolite 5 alpha-pregnan-3 alpha-ol-20-one potentiate GABA responses by acting through a common site. The site through which progesterone acts to inhibit glycine responses is distinct from the strychnine and glycine binding sites. These results not only provide an important distinction between chloride-mediated GABA and glycine responses but also suggest that endogenous progesterone or its metabolites may differentially modulate the inhibitory actions of these two neurotransmitters.

Volume 37, Issue 5, pp. 597-602, 05/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				G. Sadri-Vakili, G. C. Janis, R. C. Pierce, T. T. Gibbs, and D. H. Farb Nanomolar Concentrations of Pregnenolone Sulfate Enhance Striatal Dopamine Overflow in Vivo J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 840 - 845. [Abstract] [Full Text] [PDF]

				M. El-Etr, Y. Akwa, E.-E. Baulieu, and M. Schumacher The Neuroactive Steroid Pregnenolone Sulfate Stimulates the Release of Gonadotropin-Releasing Hormone from GT1-7 Hypothalamic Neurons, through N-Methyl-D-Aspartate Receptors Endocrinology, June 1, 2006; 147(6): 2737 - 2743. [Abstract] [Full Text] [PDF]

				S.-C. Chen, T.-J. Chang, and F.-S. Wu Competitive Inhibition of the Capsaicin Receptor-Mediated Current by Dehydroepiandrosterone in Rat Dorsal Root Ganglion Neurons J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 529 - 536. [Abstract] [Full Text] [PDF]

				J. W. Lynch Molecular Structure and Function of the Glycine Receptor Chloride Channel Physiol Rev, October 1, 2004; 84(4): 1051 - 1095. [Abstract] [Full Text] [PDF]

				C. J. Weir, A. T. Y. Ling, D. Belelli, J. A. W. Wildsmith, J. A. Peters, and J. J. Lambert The interaction of anaesthetic steroids with recombinant glycine and GABAA receptors{dagger} Br. J. Anaesth., May 1, 2004; 92(5): 704 - 711. [Abstract] [Full Text] [PDF]

				R. M. LOSEL, E. FALKENSTEIN, M. FEURING, A. SCHULTZ, H.-C. TILLMANN, K. ROSSOL-HASEROTH, and M. WEHLING Nongenomic Steroid Action: Controversies, Questions, and Answers Physiol Rev, July 1, 2003; 83(3): 965 - 1016. [Abstract] [Full Text] [PDF]

				P. Romieu, R. Martin-Fardon, W. D. Bowen, and T. Maurice sigma 1 Receptor-Related Neuroactive Steroids Modulate Cocaine-Induced Reward J. Neurosci., May 1, 2003; 23(9): 3572 - 3576. [Abstract] [Full Text] [PDF]

				A. K. Singh, B. D. Schultz, J. A. Katzenellenbogen, E. M. Price, R. J. Bridges, and N. A. Bradbury Estrogen Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator-Mediated Chloride Secretion J. Pharmacol. Exp. Ther., October 1, 2000; 295(1): 195 - 204. [Abstract] [Full Text]

				K. Paradiso, K. Sabey, A. S. Evers, C. F. Zorumski, D. F. Covey, and J. H. Steinbach Steroid Inhibition of Rat Neuronal Nicotinic alpha 4beta 2 Receptors Expressed in HEK 293 Cells Mol. Pharmacol., August 1, 2000; 58(2): 341 - 351. [Abstract] [Full Text]

				P. Follesa, M. Serra, E. Cagetti, M. G. Pisu, S. Porta, S. Floris, F. Massa, E. Sanna, and G. Biggio Allopregnanolone Synthesis in Cerebellar Granule Cells: Roles in Regulation of GABAA Receptor Expression and Function during Progesterone Treatment and Withdrawal Mol. Pharmacol., June 1, 2000; 57(6): 1262 - 1270. [Abstract] [Full Text]

				D. Haage and S. Johansson Neurosteroid Modulation of Synaptic and GABA-Evoked Currents in Neurons From the Rat Medial Preoptic Nucleus J Neurophysiol, July 1, 1999; 82(1): 143 - 151. [Abstract] [Full Text] [PDF]

				M. P. Blanton, Y. Xie, L. J. Dangott, and Jonathan. B. Cohen The Steroid Promegestone Is a Noncompetitive Antagonist of the Torpedo Nicotinic Acetylcholine Receptor that Interacts with the Lipid-Protein Interface Mol. Pharmacol., February 1, 1999; 55(2): 269 - 278. [Abstract] [Full Text]

				G. R. Ehring, H. H. Kerschbaum, C. Eder, A. L. Neben, C. M. Fanger, R. M. Khoury, P. A. Negulescu, and M. D. Cahalan A Nongenomic Mechanism for Progesterone-mediated Immunosuppression: Inhibition of K+ Channels, Ca2+ Signaling, and Gene Expression in T Lymphocytes J. Exp. Med., November 2, 1998; 188(9): 1593 - 1602. [Abstract] [Full Text] [PDF]

				C. H. R. Wetzel, B. Hermann, C. Behl, E. Pestel, G. Rammes, W. Zieglgänsberger, F. Holsboer, and R. Rupprecht Functional Antagonism of Gonadal Steroids at the 5-Hydroxytryptamine Type 3 Receptor Mol. Endocrinol., September 1, 1998; 12(9): 1441 - 1451. [Abstract] [Full Text]

				M. Beekman, J. T. Ungard, M. Gasior, R. B. Carter, D. Dijkstra, S. R. Goldberg, and J. M. Witkin Reversal of Behavioral Effects of Pentylenetetrazol by the Neuroactive Steroid Ganaxolone J. Pharmacol. Exp. Ther., March 1, 1998; 284(3): 868 - 877. [Abstract] [Full Text]

				M. Park-Chung, F.-S. Wu, R. H. Purdy, A. A. Malayev, T. T. Gibbs, and D. H. Farb Distinct Sites for Inverse Modulation of N-Methyl-D-Aspartate Receptors by Sulfated Steroids Mol. Pharmacol., December 1, 1997; 52(6): 1113 - 1123. [Abstract] [Full Text]