Function and modulation of δ-containing GABAA receptors

alphabetadelta-Containing GABA(A) receptors are (1) localized to extra- and perisynaptic membranes, (2) exhibit a high sensitivity to GABA, (3) show little desensitization, and (4) are believed to be one of the primary mediators of tonic inhibition in the central nervous system. This type of signaling appears to play a key role in controlling cell excitability. This review article briefly summarizes recent knowledge on tonic GABA-mediated inhibition. We will also consider the mechanism of action of many clinically important drugs such as anxiolytics, anticonvulsants, and sedative/hypnotics and their effects on delta-containing GABA receptor activation. We will conclude that alphabetadelta-containing GABA(A) receptors exhibit a relatively low efficacy that can be potentiated by endogenous modulators and anxiolytic agents. This scenario enables these particular GABA receptor combinations, upon neurosteroid exposure for example, to impart a profound effect on excitability in the central nervous system.

[1]  P. Whiting,et al.  Pharmacological characterization of a novel cell line expressing human α4β3δ GABAA receptors , 2002 .

[2]  F. Stephenson,et al.  Developmental Regulation of Expression of GABAA Receptor α1 and α6 Subunits in Cultured Rat Cerebellar Granule Cells , 1996, Neuropharmacology.

[3]  T. Smart,et al.  Extrasynaptic αβ subunit GABAA receptors on rat hippocampal pyramidal neurons , 2006, The Journal of physiology.

[4]  G. Homanics,et al.  The expression of GABAAβ subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells , 2008, The Journal of physiology.

[5]  T. Otis,et al.  Etomidate, propofol and the neurosteroid THDOC increase the GABA efficacy of recombinant α4β3δ and α4β3 GABAA receptors expressed in HEK cells , 2009, Neuropharmacology.

[6]  P. Somogyi,et al.  Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons , 1995, Nature.

[7]  David Attwell,et al.  Tonic and Spillover Inhibition of Granule Cells Control Information Flow through Cerebellar Cortex , 2002, Neuron.

[8]  John M. Zempel,et al.  How quickly can GABAA receptors open? , 1994, Neuron.

[9]  J. Lambert,et al.  Neurosteroids: endogenous regulators of the GABAA receptor , 2005, Nature Reviews Neuroscience.

[10]  Alastair M. Hosie,et al.  Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites , 2006, Nature.

[11]  K. Williams,et al.  Reversal of neurosteroid effects at α4β2δ GABAA receptors triggers anxiety at puberty , 2007, Nature Neuroscience.

[12]  A. Guidotti,et al.  Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Y. Ben-Ari,et al.  Paracrine Intercellular Communication by a Ca2+- and SNARE-Independent Release of GABA and Glutamate Prior to Synapse Formation , 2002, Neuron.

[14]  Ligand-Gated Ion Channel Subunit Partnerships: GABAAReceptor α6 Subunit Gene Inactivation Inhibits δ Subunit Expression , 1997, The Journal of Neuroscience.

[15]  Alastair M. Hosie,et al.  Conserved site for neurosteroid modulation of GABAA receptors , 2009, Neuropharmacology.

[16]  H. Mohler,et al.  GABAA receptor populations with novel subunit combinations and drug binding profiles identified in brain by alpha 5- and delta-subunit-specific immunopurification. , 1993, The Journal of biological chemistry.

[17]  M. Farrant,et al.  Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors , 2005, Nature Reviews Neuroscience.

[18]  R. Macdonald,et al.  Properties of putative cerebellar gamma-aminobutyric acid A receptor isoforms. , 1996, Molecular pharmacology.

[19]  D. S. Weiss,et al.  Stoichiometry of a Recombinant GABAA Receptor , 1996, The Journal of Neuroscience.

[20]  J. Lambert,et al.  Neurosteroid modulation of GABAA receptors: Molecular determinants and significance in health and disease , 2008, Neurochemistry International.

[21]  Signe í Stórustovu,et al.  Pharmacological Characterization of Agonists at δ-Containing GABAA Receptors: Functional Selectivity for Extrasynaptic Receptors Is Dependent on the Absence of γ2 , 2006, Journal of Pharmacology and Experimental Therapeutics.

[22]  W. Sieghart,et al.  Colocalization of multiple GABAA receptor subtypes with gephyrin at postsynaptic sites , 2000, The Journal of comparative neurology.

[23]  David Colquhoun,et al.  Function and structure in glycine receptors and some of their relatives , 2004, Trends in Neurosciences.

[24]  R. Olsen,et al.  Behavior and Physiology of Mice Lacking the GABAA‐Receptor δ Subunit , 2002 .

[25]  P. Somogyi,et al.  Immunoreactivity for the GABAA receptor alpha1 subunit, somatostatin and Connexin36 distinguishes axoaxonic, basket, and bistratified interneurons of the rat hippocampus. , 2007, Cerebral cortex.

[26]  I. Módy,et al.  A new naturally occurring GABAA receptor subunit partnership with high sensitivity to ethanol , 2007, Nature Neuroscience.

[27]  Edward O. Mann,et al.  Which GABAA Receptor Subunits Are Necessary for Tonic Inhibition in the Hippocampus? , 2008, The Journal of Neuroscience.

[28]  J. Steinbach,et al.  Neurosteroid Access to the GABAA Receptor , 2005, The Journal of Neuroscience.

[29]  E. Sigel,et al.  Unanticipated Structural and Functional Properties of δ-Subunit-containing GABAA Receptors* , 2009, Journal of Biological Chemistry.

[30]  H. Lester,et al.  Evidence that the M2 membrane-spanning region lines the ion channel pore of the nicotinic receptor. , 1988, Science.

[31]  W. Sieghart,et al.  Pharmacological Properties of GABAA Receptors Containing γ1 Subunits , 2006, Molecular Pharmacology.

[32]  P. Whiting,et al.  Tracazolate Reveals a Novel Type of Allosteric Interaction with Recombinant γ-Aminobutyric AcidA Receptors , 2002 .

[33]  I. Módy,et al.  Ovarian cycle–linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety , 2005, Nature Neuroscience.

[34]  Istvan Mody,et al.  Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. , 2002, Journal of neurophysiology.

[35]  G. Sperk,et al.  GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain , 2000, Neuroscience.

[36]  F. Jia,et al.  An extrasynaptic GABAA receptor mediates tonic inhibition in thalamic VB neurons. , 2005, Journal of neurophysiology.

[37]  D. Reddy.  Pharmacology of catamenial epilepsy. , 2004, Methods and findings in experimental and clinical pharmacology.

[38]  N. Zheleznova,et al.  α1β2δ, a silent GABAA receptor: recruitment by tracazolate and neurosteroids , 2008, British journal of pharmacology.

[39]  M. Bianchi,et al.  Mutation of the 9′ leucine in the GABAA receptor γ2L subunit produces an apparent decrease in desensitization by stabilizing open states without altering desensitized states , 2001, Neuropharmacology.

[40]  Maria Dorota Majewska.  Steroids and ion channels in evolution: from bacteria to synapses and mind. Evolutionary role of steroid regulation of GABA(A) receptors. , 2007, Acta neurobiologiae experimentalis.

[41]  H. Möhler,et al.  GABAA receptor diversity and pharmacology , 2006, Cell and Tissue Research.

[42]  Jon W. Johnson,et al.  Altered markers of tonic inhibition in the dorsolateral prefrontal cortex of subjects with schizophrenia. , 2009, The American journal of psychiatry.

[43]  B. L. Jones,et al.  Role of the α subunit in the modulation of GABAA receptors by anabolic androgenic steroids , 2005, Neuropharmacology.

[44]  I. Módy,et al.  Low Ethanol Concentrations Selectively Augment the Tonic Inhibition Mediated by δ Subunit-Containing GABAA Receptors in Hippocampal Neurons , 2004, The Journal of Neuroscience.

[45]  Vincenzo Crunelli,et al.  GABAA Receptor-Mediated Tonic Inhibition in Thalamic Neurons , 2005, The Journal of Neuroscience.

[46]  C. Adkins,et al.  α4β3δ GABAAReceptors Characterized by Fluorescence Resonance Energy Transfer-derived Measurements of Membrane Potential* , 2001, The Journal of Biological Chemistry.

[47]  Peter Somogyi,et al.  Segregation of Different GABAA Receptors to Synaptic and Extrasynaptic Membranes of Cerebellar Granule Cells , 1998, The Journal of Neuroscience.

[48]  Abraham Weizman,et al.  Comparison between risperidone, olanzapine, and clozapine in the management of chronic schizophrenia: a naturalistic prospective 12‐week observational study , 2006, Human psychopharmacology.

[49]  G. Metcalf,et al.  Behavioral effects of several new anxiolytics and putative anxiolytics. , 1987, European journal of pharmacology.

[50]  J. Steinbach,et al.  Activation of GABAA receptors containing the α4 subunit by GABA and pentobarbital , 2004 .

[51]  R. Olsen,et al.  Ethanol enhances α4β3δ and α6β3δ γ-aminobutyric acid type A receptors at low concentrations known to affect humans , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[52]  T. Klausberger,et al.  Subunit Composition and Quantitative Importance of Hetero-oligomeric Receptors: GABAA Receptors Containing α6 Subunits , 1998, The Journal of Neuroscience.

[53]  G. Sperk,et al.  Subunit composition, distribution and function of GABA(A) receptor subtypes. , 2002, Current topics in medicinal chemistry.

[54]  P. Somogyi,et al.  Alterations in the expression of GABAA receptor subunits in cerebellar granule cells after the disruption of the α6 subunit gene , 1999, The European journal of neuroscience.

[55]  M. Bianchi,et al.  α1 and α6 subunits specify distinct desensitization, deactivation and neurosteroid modulation of GABAA receptors containing the δ subunit , 2002, Neuropharmacology.

[56]  R. Mckernan,et al.  Which GABAA-receptor subtypes really occur in the brain? , 1996, Trends in Neurosciences.

[57]  I. Módy,et al.  Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABAA receptors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[58]  J. Barker,et al.  Cl− channels are randomly activated by continuous GABA secretion in cultured embryonic rat hippocampal neurons , 1993, Neuroscience Letters.

[59]  A. Kriegstein,et al.  Changing properties of GABA(A) receptor-mediated signaling during early neocortical development. , 1999, Journal of neurophysiology.

[60]  H. Goodkin,et al.  Cultured Hippocampal Pyramidal Neurons Express Two Kinds of GABAA Receptors , 2005, Molecular Pharmacology.

[61]  R. Mckernan,et al.  theta, a novel gamma-aminobutyric acid type A receptor subunit. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[62]  K. Wafford,et al.  Gaboxadol--a new awakening in sleep. , 2006, Current opinion in pharmacology.

[63]  R. Rupprecht,et al.  Neuroactive Steroids in Depression and Anxiety Disorders: Clinical Studies , 2007, Neuroendocrinology.

[64]  J. Fisher,et al.  Single channel properties of recombinant GABAA receptors containing γ2 or δ subtypes expressed with α1 and β3 subtypes in mouse L929 Cells , 1997, The Journal of physiology.

[65]  Robert A Pearce,et al.  Active and Passive Membrane Properties and Intrinsic Kinetics Shape Synaptic Inhibition in Hippocampal CA1 Pyramidal Neurons , 2006, The Journal of Neuroscience.

[66]  K. Wohlfarth,et al.  Enhanced Neurosteroid Potentiation of Ternary GABAAReceptors Containing the δ Subunit , 2002, The Journal of Neuroscience.

[67]  E A Barnard,et al.  International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. , 1998, Pharmacological reviews.

[68]  W. Sieghart,et al.  Distribution of α1, α4, γ2, and δ subunits of GABAA receptors in hippocampal granule cells , 2004, Brain Research.

[69]  Alexey Semyanov,et al.  Regulation of excitability by extrasynaptic GABA(A) receptors. , 2008, Results and problems in cell differentiation.

[70]  Istvan Mody,et al.  Perisynaptic Localization of δ Subunit-Containing GABAA Receptors and Their Activation by GABA Spillover in the Mouse Dentate Gyrus , 2003, The Journal of Neuroscience.

[71]  Jun Zhang,et al.  Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro , 2005, Brain Research Bulletin.