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J. Biol. Chem., Vol. 278, Issue 40, 38637-38645, October 3, 2003

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Asymmetric Cross-inhibition between GABA_A and Glycine Receptors in Rat Spinal Dorsal Horn Neurons^*

Yong Li  , Long-Jun Wu , Pascal Legendre ¶ || and Tian-Le Xu  || **

From the Department of Neurobiology and Biophysics, University of Science and Technology of China, Hefei 230027 and Institute of Neuroscience, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China and the ^¶UMR CNRS 7102 Neurobiologie des Processus Adaptatifs, Université Pierre et Marie Curie, Paris 75252 cedex 05, France

Presynaptic nerve terminals of inhibitory synapses in the dorsal horn of the spinal cord and brain stem can release both GABA and glycine, leading to coactivation of postsynaptic GABA_A and glycine receptors. In the present study we have analyzed functional interactions between GABA_A and glycine receptors in acutely dissociated neurons from rat sacral dorsal commissural nucleus. Although the application of GABA and glycine activates pharmacologically distinct receptors, the current induced by a simultaneous application of these two transmitters was less than the sum of currents induced by applying two transmitters separately. Sequential application of glycine and GABA revealed that the GABA-evoked current is more affected by glycine than glycineevoked responses by GABA. Activation of glycine receptors decreased the amplitude and accelerated the rate of desensitization of GABA-induced currents. This asymmetric cross-inhibition is reversible, dependent on the agonist concentration applied, but independent of both membrane potential and intracellular calcium concentration or changes in the chloride equilibrium potential. During sequential applications, the asymmetric cross-inhibition was prevented by selective GABA_A or glycine receptor antagonists, suggesting that occupation of binding sites did not suffice to induce glycine and GABA_A receptors functional interaction, and receptor channel activation is required. Furthermore, inhibition of phosphatase 2B, but not phosphatase 1 or 2A, prevented GABA_A receptor inhibition by glycine receptor activation, whereas inhibition of phosphorylation pathways rendered cross-talk irreversible. Taken together, our results demonstrated that there is an asymmetric cross-inhibition between glycine and GABA_A receptors and that a selective modulation of the state of phosphorylation of GABA_A receptor and/or mediator proteins underlies the asymmetry in the cross-inhibition.

Received for publication, April 9, 2003 , and in revised form, June 16, 2003.

^* This work was supported by Knowledge Innovation Project Grant KSCX 2-2-04 from the Chinese Academy of Sciences, National Basic Research Program of China Grant G1999054000, and National Natural Science Foundation of China Grants 30170247 and 30125015 (to T.-L. X.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

International Brain Research Organization outstanding fellow of 2003. Submitted in partial fulfillment of the requirements for a Ph.D. at the University of Science and Technology of China.

^|| Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Inst. of Neuroscience, Shanghai Insts. of Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Rd., Shanghai 200031, China. Tel.: 86-21-5492-1751; Fax: 86-21-5492-1735; E-mail: tlxu{at}ion.ac.cn.

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