QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (27) Citing Articles via Google Scholar Google Scholar Articles by Barberis, A. Articles by Mozrzymas, J. W. Search for Related Content PubMed PubMed Citation Articles by Barberis, A. Articles by Mozrzymas, J. W.

 Previous Article  |  Next Article 

The Journal of Neuroscience, December 1, 2000, 20(23):8618-8627

Zinc Inhibits Miniature GABAergic Currents by Allosteric Modulation of GABA_A Receptor Gating

Andrea Barberis¹, Enrico Cherubini¹, and Jerzy W. Mozrzymas^{1, 2}

¹ Neuroscience Program and Istituto Nazionale Fisica della Materia Unit, International School for Advanced Studies (SISSA), 34014 Trieste, Italy, and ² Department of Biophysics, Wroclaw University of Medicine, 50-368 Wroclaw, Poland

Zinc is abundantly present in the CNS, and after nerve stimulation is thought to be released in sufficient quantity to modulate the synaptic transmission. Although it is known that this divalent cation inhibits the GABAergic synaptic currents, the underlying mechanisms were not fully elucidated. Here we report that zinc reduced the amplitude, slowed the rise time, and accelerated the decay of mIPSCs in cultured hippocampal neurons. The analysis of current responses to rapid GABA applications and model simulations indicated that these effects on mIPSCs are caused by zinc modulation of GABA_A receptor gating. In particular, zinc slowed the onset of GABA-evoked currents by decreasing both the binding (k_on) and the transition rate from closed to open state (₂). Moreover, slower onset and recovery from desensitization as well as an increased unbinding rate (k_off) were shown to underlie the accelerated deactivation kinetics in the presence of zinc. The nonequilibrium conditions of GABA_A receptor activation were found to strongly affect zinc modulation of this receptor. In particular, an extremely fast clearance of synaptic GABA is implicated to be responsible for a stronger zinc effect on mIPSCs than on current responses to exogenous GABA. Finally, the analysis of currents evoked by GABA coapplied with zinc indicated that the interaction between zinc and GABA_A receptors was too slow to explain zinc effects in terms of competitive antagonism. In conclusion, our results provide evidence that inhibition of mIPSCs by zinc is attributable to the allosteric modulation of GABA_A receptor gating.

Key words: mIPSCs; GABA_A receptors; -alanine; fast perfusion; nonequilibrium conditions; kinetics analysis; hippocampus; cell cultures

---

Copyright © 2000 Society for Neuroscience  0270-6474/00/20238618-10$05.00/0

This article has been cited by other articles:

				J.-M. Mangin, L. Nguyen, C. Gougnard, G. Hans, B. Rogister, S. Belachew, G. Moonen, P. Legendre, and J.-M. Rigo Developmental Regulation of {beta}-Carboline-Induced Inhibition of Glycine-Evoked Responses Depends on Glycine Receptor {beta} Subunit Expression Mol. Pharmacol., May 1, 2005; 67(5): 1783 - 1796. [Abstract] [Full Text] [PDF]

				E. Cohen-Kfir, W. Lee, S. Eskandari, and N. Nelson Zinc inhibition of {gamma}-aminobutyric acid transporter 4 (GAT4) reveals a link between excitatory and inhibitory neurotransmission PNAS, April 26, 2005; 102(17): 6154 - 6159. [Abstract] [Full Text] [PDF]

				A. Barberis, C. Lu, S. Vicini, and J. W. Mozrzymas Developmental Changes of GABA Synaptic Transient in Cerebellar Granule Cells Mol. Pharmacol., April 1, 2005; 67(4): 1221 - 1228. [Abstract] [Full Text] [PDF]

				T. G. Smart, A. M. Hosie, and P. S. Miller Zn2+ Ions: Modulators of Excitatory and Inhibitory Synaptic Activity Neuroscientist, October 1, 2004; 10(5): 432 - 442. [Abstract] [PDF]

				J. W. Mozrzymas, E. D. Zarmowska, M. Pytel, and K. Mercik Modulation of GABAA Receptors by Hydrogen Ions Reveals Synaptic GABA Transient and a Crucial Role of the Desensitization Process J. Neurosci., September 3, 2003; 23(22): 7981 - 7992. [Abstract] [Full Text] [PDF]

				E. M. Petrini, P. Zacchi, A. Barberis, J. W. Mozrzymas, and E. Cherubini Declusterization of GABAA Receptors Affects the Kinetic Properties of GABAergic Currents in Cultured Hippocampal Neurons J. Biol. Chem., April 25, 2003; 278(18): 16271 - 16279. [Abstract] [Full Text] [PDF]

				J. W. Mozrzymas, A. Barberis, K. Mercik, and E. D. Zarnowska Binding Sites, Singly Bound States, and Conformation Coupling Shape GABA-Evoked Currents J Neurophysiol, February 1, 2003; 89(2): 871 - 883. [Abstract] [Full Text] [PDF]

				G. Swaminath, J. Steenhuis, B. Kobilka, and T. W. Lee Allosteric Modulation of beta 2-Adrenergic Receptor by Zn2+ Mol. Pharmacol., January 1, 2002; 61(1): 65 - 72. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help