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 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 Web of Science (54) Citing Articles via Google Scholar Google Scholar Articles by Mozrzymas, J. W. Articles by Cherubini, E. Search for Related Content PubMed PubMed Citation Articles by Mozrzymas, J. W. Articles by Cherubini, E.

 Previous Article  |  Next Article 

The Journal of Neuroscience, April 1, 1999, 19(7):2474-2488

Chlorpromazine Inhibits Miniature GABAergic Currents by Reducing the Binding and by Increasing the Unbinding Rate of GABA_A Receptors

Jerzy W. Mozrzymas^{1, 2}, Andrea Barberis¹, Krystyna Michalak², and Enrico Cherubini¹

¹ Neuroscience Program and Istituto Nazionale Fisica della Materia Unit, International School for Advanced Studies, 34 014 Trieste, Italy, and ² Department of Biophysics, Wroclaw University of Medicine, 50 368 Wroclaw, Poland

Recent studies have emphasized that nonequilibrium conditions of postsynaptic GABA_A receptor (GABA_AR) activation is a key factor in shaping the time course of IPSCs (Puia et al., 1994; Jones and Westbrook, 1995). Such nonequilibrium, resulting from extremely fast agonist time course, may affect the interaction between pharmacological agents and postsynaptic GABA_ARs. In the present study we found that chlorpromazine (CPZ), a widely used antipsychotic drug known to interfere with several ligand and voltage-gated channels, reduces the amplitude and accelerates the decay of miniature IPSCs (mIPSCs). A good qualitative reproduction of the effects of CPZ on mIPSCs was obtained when mIPSCs were mimicked by responses to ultrafast GABA applications to excised patches. Our experimental data and model simulations indicate that CPZ affects mIPSCs by decreasing the binding (k_on) and by increasing the unbinding (k_off) rates of GABA_ARs. Because of reduction of k_on by CPZ, the binding reaction becomes rate-limiting, and agonist exposure of GABA_ARs during mIPSC is too short to activate the receptors to the same extent as in control conditions. The increase in unbinding rate is implicated as the mechanism underlying the acceleration of mIPSC decaying phase. The effect of CPZ on GABA_AR binding rate, resulting in slower onset of GABA-evoked currents, provides a tool to estimate the speed of synaptic clearance of GABA. Moreover, the onset kinetics of recorded responses allowed the estimate the peak synaptic GABA concentration.

Key words: chlorpromazine; GABA_A receptors; miniature IPSCs; patch-clamp; binding and unbinding rate constants; hippocampus

---

Copyright © 1999 Society for Neuroscience  0270-6474/99/1972474-15$05.00/0

This article has been cited by other articles:

				C. A. A. Penatti, D. M. Porter, and L. P. Henderson Chronic Exposure to Anabolic Androgenic Steroids Alters Neuronal Function in the Mammalian Forebrain via Androgen Receptor- and Estrogen Receptor-Mediated Mechanisms J. Neurosci., October 7, 2009; 29(40): 12484 - 12496. [Abstract] [Full Text] [PDF]

				J. W. Mozrzymas, T. Wojtowicz, M. Piast, K. Lebida, P. Wyrembek, and K. Mercik GABA transient sets the susceptibility of mIPSCs to modulation by benzodiazepine receptor agonists in rat hippocampal neurons J. Physiol., November 15, 2007; 585(1): 29 - 46. [Abstract] [Full Text] [PDF]

				C. M. Schofield and J. R. Huguenard GABA Affinity Shapes IPSCs in Thalamic Nuclei J. Neurosci., July 25, 2007; 27(30): 7954 - 7962. [Abstract] [Full Text] [PDF]

				A. A. Biro, N. B. Holderith, and Z. Nusser Release Probability-Dependent Scaling of the Postsynaptic Responses at Single Hippocampal GABAergic Synapses J. Neurosci., November 29, 2006; 26(48): 12487 - 12496. [Abstract] [Full Text] [PDF]

				B. Eisensamer, M. Uhr, S. Meyr, G. Gimpl, T. Deiml, G. Rammes, J. J. Lambert, W. Zieglgansberger, F. Holsboer, and R. Rupprecht Antidepressants and Antipsychotic Drugs Colocalize with 5-HT3 Receptors in Raft-Like Domains J. Neurosci., November 2, 2005; 25(44): 10198 - 10206. [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]

				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]

				G. B. Richerson and Y. Wu Dynamic Equilibrium of Neurotransmitter Transporters: Not Just for Reuptake Anymore J Neurophysiol, September 1, 2003; 90(3): 1363 - 1374. [Abstract] [Full Text] [PDF]

				L. N Eisenman, Y. He, C. Fields, C. F Zorumski, and S. Mennerick Activation-Dependent Properties of Pregnenolone Sulfate Inhibition of GABAA Receptor-Mediated Current J. Physiol., August 1, 2003; 550(3): 679 - 691. [Abstract] [Full Text] [PDF]

				A. Skorinkin, A. Nistri, and R. Giniatullin Bimodal Action of Protons on ATP Currents of Rat PC12 Cells J. Gen. Physiol., June 30, 2003; 122(1): 33 - 44. [Abstract] [Full Text] [PDF]

				I. Dean, S. J. Robertson, and F. A. Edwards Serotonin Drives a Novel GABAergic Synaptic Current Recorded in Rat Cerebellar Purkinje Cells: A Lugaro Cell to Purkinje Cell Synapse J. Neurosci., June 1, 2003; 23(11): 4457 - 4469. [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]

				A. Barberis, E. Cherubini, and J. W. Mozrzymas Zinc Inhibits Miniature GABAergic Currents by Allosteric Modulation of GABAA Receptor Gating J. Neurosci., December 1, 2000; 20(23): 8618 - 8627. [Abstract] [Full Text] [PDF]

				L. S. Overstreet, M. V. Jones, and G. L. Westbrook Slow Desensitization Regulates the Availability of Synaptic GABAA Receptors J. Neurosci., November 1, 2000; 20(21): 7914 - 7921. [Abstract] [Full Text] [PDF]

				W. Shen, S. Mennerick, D. F. Covey, and C. F. Zorumski Pregnenolone Sulfate Modulates Inhibitory Synaptic Transmission by Enhancing GABAA Receptor Desensitization J. Neurosci., May 15, 2000; 20(10): 3571 - 3579. [Abstract] [Full Text] [PDF]

				M. I. Banks and R. A. Pearce Kinetic Differences between Synaptic and Extrasynaptic GABAA Receptors in CA1 Pyramidal Cells J. Neurosci., February 1, 2000; 20(3): 937 - 948. [Abstract] [Full Text] [PDF]

				D. Bai, P. S. Pennefather, J. F. MacDonald, and B. A. Orser The General Anesthetic Propofol Slows Deactivation and Desensitization of GABAA Receptors J. Neurosci., December 15, 1999; 19(24): 10635 - 10646. [Abstract] [Full Text] [PDF]

				Z. Nusser, W. Sieghart, and I. Mody Differential regulation of synaptic GABAA receptors by cAMP-dependent protein kinase in mouse cerebellar and olfactory bulb neurones J. Physiol., December 1, 1999; 521(2): 421 - 435. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help