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 (100) Citing Articles via Google Scholar Google Scholar Articles by Jones, M. V. Articles by Westbrook, G. L. Search for Related Content PubMed PubMed Citation Articles by Jones, M. V. Articles by Westbrook, G. L.

 Previous Article  |  Next Article 

Volume 17, Number 20, Issue of October 15, 1997 pp. 7626-7633
Copyright ©1997 Society for Neuroscience

Shaping of IPSCs by Endogenous Calcineurin Activity

Received June 27, 1997; revised July 24, 1997; accepted July 28, 1997.

Mathew V. Jones¹ and Gary L. Westbrook^{1, 2}

¹ The Vollum Institute and ² Department of Neurology, Oregon Health Sciences University, Portland, Oregon 97201

Synaptic inhibition, mediated by GABA_A receptors, regulates neuronal firing, influences coincidence detection (), and can synchronize the output of neural circuits (). Although GABA_A receptors can be modulated by phosphorylation, few studies have directly addressed the role of such modulation at synapses, where the nonequilibrium conditions of receptor activation are quite different from those often used to study GABA_A receptors in vitro. Here we promoted endogenous phosphorylation by inhibiting specific phosphatases in rat hippocampal neurons and compared the effects on IPSCs with GABA_A channel responses in outside-out patches. Brief and saturating GABA pulses (5 msec; 10 mM) activated patch currents resembling the IPSC. Inhibition of calcineurin (protein phosphatase 2B), but not phosphatases 1 or 2A, produced a similar shortening of IPSC and patch responses, as did nonspecific inhibition of dephosphorylation using ATPS or high concentrations of intracellular phosphate. Calcineurin inhibition increased the microscopic ligand unbinding rate, which was measured using the competitive antagonist 2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium bromide, suggesting that the IPSC shortening was partly caused by destabilization of the ligand binding site. Calcineurin inhibition also increased the rate and extent of macroscopic receptor desensitization. These results show that endogenous regulation by kinases and calcineurin can produce substantial changes in the IPSC duration by altering the unbinding and gating kinetics of the GABA_A receptor. Dynamic regulation of synaptic inhibition may thus allow for the tuning of circuit behavior at the level of individual inhibitory synapses.

Key words: GABA_A receptor; synapse; phosphorylation; modulation; kinetics; hippocampus

This article has been cited by other articles:

				C. M. Houston, A. M. Hosie, and T. G. Smart Distinct Regulation of {beta}2 and {beta}3 Subunit-Containing Cerebellar Synaptic GABAA Receptors by Calcium/Calmodulin-Dependent Protein Kinase II J. Neurosci., July 23, 2008; 28(30): 7574 - 7584. [Abstract] [Full Text] [PDF]

				H.-J. Feng, G. C. Mathews, C. Kao, and R. L. Macdonald Alterations of GABAA-Receptor Function and Allosteric Modulation During Development of Status Epilepticus J Neurophysiol, March 1, 2008; 99(3): 1285 - 1293. [Abstract] [Full Text] [PDF]

				D. R. Peden, C. M. Petitjean, M. B. Herd, M. S. Durakoglugil, T. W. Rosahl, K. Wafford, G. E. Homanics, D. Belelli, J.-M. Fritschy, and J. J. Lambert Developmental maturation of synaptic and extrasynaptic GABAA receptors in mouse thalamic ventrobasal neurones J. Physiol., February 15, 2008; 586(4): 965 - 987. [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]

				M. M. Huntsman and J. R. Huguenard Fast IPSCs in rat thalamic reticular nucleus require the GABAA receptor {beta}1 subunit J. Physiol., April 15, 2006; 572(2): 459 - 475. [Abstract] [Full Text] [PDF]

				Y.-C. Yu, L.-H. Cao, and X.-L. Yang Modulation by Brain Natriuretic Peptide of GABA Receptors on Rat Retinal ON-Type Bipolar Cells J. Neurosci., January 11, 2006; 26(2): 696 - 707. [Abstract] [Full Text] [PDF]

				D. E. Naylor, H. Liu, and C. G. Wasterlain Trafficking of GABAA Receptors, Loss of Inhibition, and a Mechanism for Pharmacoresistance in Status Epilepticus J. Neurosci., August 24, 2005; 25(34): 7724 - 7733. [Abstract] [Full Text] [PDF]

				L. W. J. Bosman, K. Heinen, S. Spijker, and A. B. Brussaard Mice Lacking the Major Adult GABAA Receptor Subtype Have Normal Number of Synapses, But Retain Juvenile IPSC Kinetics Until Adulthood J Neurophysiol, July 1, 2005; 94(1): 338 - 346. [Abstract] [Full Text] [PDF]

				H. P. Goodkin, J.-L. Yeh, and J. Kapur Status Epilepticus Increases the Intracellular Accumulation of GABAA Receptors J. Neurosci., June 8, 2005; 25(23): 5511 - 5520. [Abstract] [Full Text] [PDF]

				R. Kovacs, J. Kardos, U. Heinemann, and O. Kann Mitochondrial Calcium Ion and Membrane Potential Transients Follow the Pattern of Epileptiform Discharges in Hippocampal Slice Cultures J. Neurosci., April 27, 2005; 25(17): 4260 - 4269. [Abstract] [Full Text] [PDF]

				S. S Smith and Q. H. Gong Neurosteroid administration and withdrawal alter GABAA receptor kinetics in CA1 hippocampus of female rats J. Physiol., April 15, 2005; 564(2): 421 - 436. [Abstract] [Full Text] [PDF]

				R. M. Sanchez, W. Dai, R. E. Levada, J. J. Lippman, and F. E. Jensen AMPA/Kainate Receptor-Mediated Downregulation of GABAergic Synaptic Transmission by Calcineurin after Seizures in the Developing Rat Brain J. Neurosci., March 30, 2005; 25(13): 3442 - 3451. [Abstract] [Full Text] [PDF]

				J. J. Laschet, F. Minier, I. Kurcewicz, M. H. Bureau, S. Trottier, F. Jeanneteau, N. Griffon, B. Samyn, J. Van Beeumen, J. Louvel, et al. Glyceraldehyde-3-Phosphate Dehydrogenase Is a GABAA Receptor Kinase Linking Glycolysis to Neuronal Inhibition J. Neurosci., September 1, 2004; 24(35): 7614 - 7622. [Abstract] [Full Text] [PDF]

				J. N. Jovanovic, P. Thomas, J. T. Kittler, T. G. Smart, and S. J. Moss Brain-Derived Neurotrophic Factor Modulates Fast Synaptic Inhibition by Regulating GABAA Receptor Phosphorylation, Activity, and Cell-Surface Stability J. Neurosci., January 14, 2004; 24(2): 522 - 530. [Abstract] [Full Text] [PDF]

				D. J. Hinkle and R. L. Macdonald {beta} Subunit Phosphorylation Selectively Increases Fast Desensitization and Prolongs Deactivation of {alpha}1{beta}1{gamma}2L and {alpha}1{beta}3{gamma}2L GABAA Receptor Currents J. Neurosci., December 17, 2003; 23(37): 11698 - 11710. [Abstract] [Full Text] [PDF]

				A. Bacci, U. Rudolph, J. R. Huguenard, and D. A. Prince Major Differences in Inhibitory Synaptic Transmission onto Two Neocortical Interneuron Subclasses J. Neurosci., October 22, 2003; 23(29): 9664 - 9674. [Abstract] [Full Text] [PDF]

				Y. Li, L.-J. Wu, P. Legendre, and T.-L. Xu Asymmetric Cross-inhibition between GABAA and Glycine Receptors in Rat Spinal Dorsal Horn Neurons J. Biol. Chem., October 3, 2003; 278(40): 38637 - 38645. [Abstract] [Full Text] [PDF]

				F.-C. Hsu, R. Waldeck, D. S. Faber, and S. S. Smith Neurosteroid Effects on GABAergic Synaptic Plasticity in Hippocampus J Neurophysiol, April 1, 2003; 89(4): 1929 - 1940. [Abstract] [Full Text] [PDF]

				C.-H. Lin, S.-H. Yeh, T.-H. Leu, W.-C. Chang, S.-T. Wang, and P.-W. Gean Identification of Calcineurin as a Key Signal in the Extinction of Fear Memory J. Neurosci., March 1, 2003; 23(5): 1574 - 1579. [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]

				J.-J. Koksma, R. E. van Kesteren, T. W. Rosahl, R. Zwart, A. B. Smit, H. Luddens, and A. B. Brussaard Oxytocin Regulates Neurosteroid Modulation of GABAA Receptors in Supraoptic Nucleus around Parturition J. Neurosci., February 1, 2003; 23(3): 788 - 797. [Abstract] [Full Text] [PDF]

				J. Wang, S. Liu, U. Haditsch, W. Tu, K. Cochrane, G. Ahmadian, L. Tran, J. Paw, Y. Wang, I. Mansuy, et al. Interaction of Calcineurin and Type-A GABA Receptor gamma 2 Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses J. Neurosci., February 1, 2003; 23(3): 826 - 836. [Abstract] [Full Text] [PDF]

				L. W J Bosman, T. W Rosahl, and A. B Brussaard Neonatal development of the rat visual cortex: synaptic function of GABAa receptor {alpha} subunits J. Physiol., November 15, 2002; 545(1): 169 - 181. [Abstract] [Full Text] [PDF]

				M. T Bianchi and R. L Macdonald Slow phases of GABAA receptor desensitization: structural determinants and possible relevance for synaptic function J. Physiol., October 1, 2002; 544(1): 3 - 18. [Abstract] [Full Text] [PDF]

				L. J Gentet and J. D Clements Binding site stoichiometry and the effects of phosphorylation on human {alpha}1 homomeric glycine receptors J. Physiol., October 1, 2002; 544(1): 97 - 106. [Abstract] [Full Text] [PDF]

				J. Snellman and S. Nawy Regulation of the Retinal Bipolar Cell mGluR6 Pathway by Calcineurin J Neurophysiol, September 1, 2002; 88(3): 1088 - 1096. [Abstract] [Full Text] [PDF]

				M. E. Calcagnotto, M. F. Paredes, and S. C. Baraban Heterotopic Neurons with Altered Inhibitory Synaptic Function in an Animal Model of Malformation-Associated Epilepsy J. Neurosci., September 1, 2002; 22(17): 7596 - 7605. [Abstract] [Full Text] [PDF]

				J. P. Dilger The effects of general anaesthetics on ligand-gated ion channels Br. J. Anaesth., July 1, 2002; 89(1): 41 - 51. [Abstract] [Full Text] [PDF]

				S.-y. Kawaguchi and T. Hirano Signaling Cascade Regulating Long-Term Potentiation of GABAA Receptor Responsiveness in Cerebellar Purkinje Neurons J. Neurosci., May 15, 2002; 22(10): 3969 - 3976. [Abstract] [Full Text] [PDF]

				M. Wang, Y. He, L. N. Eisenman, C. Fields, C.-M. Zeng, J. Mathews, A. Benz, T. Fu, E. Zorumski, J. H. Steinbach, et al. 3beta -Hydroxypregnane Steroids Are Pregnenolone Sulfate-Like GABAA Receptor Antagonists J. Neurosci., May 1, 2002; 22(9): 3366 - 3375. [Abstract] [Full Text] [PDF]

				I Aradi and I Soltesz Modulation of network behaviour by changes in variance in interneuronal properties J. Physiol., January 1, 2002; 538(1): 227 - 251. [Abstract] [Full Text] [PDF]

				J. R. Mellor and A. D. Randall Synaptically Released Neurotransmitter Fails to Desensitize Postsynaptic GABAA Receptors in Cerebellar Cultures J Neurophysiol, May 1, 2001; 85(5): 1847 - 1857. [Abstract] [Full Text] [PDF]

				S. Lei, B. A. Orser, G. R. L. Thatcher, J. N. Reynolds, and J. F. MacDonald Positive Allosteric Modulators of AMPA Receptors Reduce Proton-Induced Receptor Desensitization in Rat Hippocampal Neurons J Neurophysiol, May 1, 2001; 85(5): 2030 - 2038. [Abstract] [Full Text] [PDF]

				M. Bartos, I. Vida, M. Frotscher, J. R. P. Geiger, and P. Jonas Rapid Signaling at Inhibitory Synapses in a Dentate Gyrus Interneuron Network J. Neurosci., April 15, 2001; 21(8): 2687 - 2698. [Abstract] [Full Text] [PDF]

				T.-p. Yu, S. McKinney, H. A. Lester, and N. Davidson gamma -Aminobutyric acid type A receptors modulate cAMP-mediated long-term potentiation and long-term depression at monosynaptic CA3-CA1 synapses PNAS, April 5, 2001; (2001) 91093998. [Abstract] [Full Text]

				A. Devor, J.-M. Fritschy, and Y. Yarom Spatial Distribution and Subunit Composition of GABAA Receptors in the Inferior Olivary Nucleus J Neurophysiol, April 1, 2001; 85(4): 1686 - 1696. [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]

				L. Chen, H. Wang, S. Vicini, and R. W. Olsen The gamma -aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) promotes GABAA receptor clustering and modulates the channel kinetics PNAS, September 8, 2000; (2000) 190133497. [Abstract] [Full Text]

				S. Nawy Regulation of the On Bipolar Cell mGluR6 Pathway by Ca2+ J. Neurosci., June 15, 2000; 20(12): 4471 - 4479. [Abstract] [Full Text] [PDF]

				A. Fancsik, D. M. Linn, and J. G. Tasker Neurosteroid Modulation of GABA IPSCs Is Phosphorylation Dependent J. Neurosci., May 1, 2000; 20(9): 3067 - 3075. [Abstract] [Full Text] [PDF]

				G. Maccaferri, J David, B Roberts, P. Szucs, C. A Cottingham, and P. Somogyi Cell surface domain specific postsynaptic currents evoked by identified GABAergic neurones in rat hippocampus in vitro J. Physiol., April 1, 2000; 524(1): 91 - 116. [Abstract] [Full Text] [PDF]

				X. Li and R. A. Pearce Effects of Halothane on GABAA Receptor Kinetics: Evidence for Slowed Agonist Unbinding J. Neurosci., February 1, 2000; 20(3): 899 - 907. [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]

				M. M. Huntsman and J. R. Huguenard Nucleus-Specific Differences in GABAA-Receptor-Mediated Inhibition Are Enhanced During Thalamic Development J Neurophysiol, January 1, 2000; 83(1): 350 - 358. [Abstract] [Full Text] [PDF]

				B. Hutcheon, P. Morley, and M. O Poulter Developmental change in GABAA receptor desensitization kinetics and its role in synapse function in rat cortical neurons J. Physiol., January 1, 2000; 522(1): 3 - 17. [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]

				D. D. Dunning, C. L. Hoover, I. Soltesz, M. A. Smith, and D. K. O'Dowd GABAA Receptor-Mediated Miniature Postsynaptic Currents and alpha -Subunit Expression in Developing Cortical Neurons J Neurophysiol, December 1, 1999; 82(6): 3286 - 3297. [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]

				S. G. Brickley, S. G. Cull-Candy, and M. Farrant Single-Channel Properties of Synaptic and Extrasynaptic GABAA Receptors Suggest Differential Targeting of Receptor Subtypes J. Neurosci., April 15, 1999; 19(8): 2960 - 2973. [Abstract] [Full Text] [PDF]

				J. W. Mozrzymas, A. Barberis, K. Michalak, and E. Cherubini Chlorpromazine Inhibits Miniature GABAergic Currents by Reducing the Binding and by Increasing the Unbinding Rate of GABAA Receptors J. Neurosci., April 1, 1999; 19(7): 2474 - 2488. [Abstract] [Full Text] [PDF]

				M. M. Huntsman, D. M. Porcello, G. E. Homanics, T. M. DeLorey, and J. R. Huguenard Reciprocal Inhibitory Connections and Network Synchrony in the Mammalian Thalamus Science, January 22, 1999; 283(5401): 541 - 543. [Abstract] [Full Text]

				D. Perrais and N. Ropert Effect of Zolpidem on Miniature IPSCs and Occupancy of Postsynaptic GABAA Receptors in Central Synapses J. Neurosci., January 15, 1999; 19(2): 578 - 588. [Abstract] [Full Text] [PDF]

				P. Poisbeau, M. C. Cheney, M. D. Browning, and I. Mody Modulation of Synaptic GABAA Receptor Function by PKA and PKC in Adult Hippocampal Neurons J. Neurosci., January 15, 1999; 19(2): 674 - 683. [Abstract] [Full Text] [PDF]

				K. F Haas and R. L Macdonald GABAA receptor subunit {gamma}2 and {delta} subtypes confer unique kinetic properties on recombinant GABAA receptor currents in mouse fibroblasts J. Physiol., January 1, 1999; 514(1): 27 - 45. [Abstract] [Full Text] [PDF]

				M. V. Jones, Y. Sahara, J. A. Dzubay, and G. L. Westbrook Defining Affinity with the GABAA Receptor J. Neurosci., November 1, 1998; 18(21): 8590 - 8604. [Abstract] [Full Text] [PDF]

				W. J. Zhu, J. F. Wang, L. Corsi, and S. Vicini Lanthanum-mediated modification of GABAA receptor deactivation, desensitization and inhibitory synaptic currents in rat cerebellar neurons J. Physiol., September 15, 1998; 511(3): 647 - 661. [Abstract] [Full Text] [PDF]

				A. Akopian, R. Gabriel, and P. Witkovsky Calcium Released From Intracellular Stores Inhibits GABAA-Mediated Currents in Ganglion Cells of the Turtle Retina J Neurophysiol, September 1, 1998; 80(3): 1105 - 1115. [Abstract] [Full Text] [PDF]

				J R Mellor and A D Randall Voltage-dependent deactivation and desensitization of GABA responses in cultured murine cerebellar granule cells J. Physiol., January 15, 1998; 506(2): 377 - 390. [Abstract] [Full Text] [PDF]

				N. J. Brandon, P. Delmas, J. T. Kittler, B. J. McDonald, W. Sieghart, D. A. Brown, T. G. Smart, and S. J. Moss GABAA Receptor Phosphorylation and Functional Modulation in Cortical Neurons by a Protein Kinase C-dependent Pathway J. Biol. Chem., December 1, 2000; 275(49): 38856 - 38862. [Abstract] [Full Text] [PDF]

				T.-p. Yu, S. McKinney, H. A. Lester, and N. Davidson gamma -Aminobutyric acid type A receptors modulate cAMP-mediated long-term potentiation and long-term depression at monosynaptic CA3-CA1 synapses PNAS, April 24, 2001; 98(9): 5264 - 5269. [Abstract] [Full Text] [PDF]

				L. Chen, H. Wang, S. Vicini, and R. W. Olsen From the Cover: The gamma -aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) promotes GABAA receptor clustering and modulates the channel kinetics PNAS, October 10, 2000; 97(21): 11557 - 11562. [Abstract] [Full Text] [PDF]

				I. Aradi and I. Soltesz Modulation of network behaviour by changes in variance in interneuronal properties J. Physiol., December 3, 2001; (2001) 200101305. [Abstract] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help