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 (144) Citing Articles via Google Scholar Google Scholar Articles by Whiting, P. J. Articles by Wafford, K. A. Search for Related Content PubMed PubMed Citation Articles by Whiting, P. J. Articles by Wafford, K. A. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Nucleotide Protein UniGene

 Previous Article  |  Next Article 

Volume 17, Number 13, Issue of July 1, 1997 pp. 5027-5037
Copyright ©1997 Society for Neuroscience

Neuronally Restricted RNA Splicing Regulates the Expression of a Novel GABA_A Receptor Subunit Conferring Atypical Functional Properties

Received Feb. 19, 1997; revised April 7, 1997; accepted April 10, 1997.

Paul J. Whiting¹, George McAllister¹, Demetrios Vassilatis², Timothy P. Bonnert¹, Robert P. Heavens¹, David W. Smith¹, Louise Hewson¹, Ruth O'Donnell¹, Michael R. Rigby¹, Dalip J. S. Sirinathsinghji¹, George Marshall¹, Sally A. Thompson¹, and Keith A. Wafford¹

¹ Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Harlow, Essex CM20 2QR, United Kingdom, and ² Merck Research Laboratories, Rahway, New Jersey 07065

We report the isolation and characterization of a cDNA encoding a novel member of the GABA receptor gene family, . This polypeptide is 506 amino acids in length and exhibits its greatest amino acid sequence identity with the GABA_A receptor 3 subunit (47%), although this degree of homology is not sufficient for it to be classified as a fourth  subunit. The  subunit coassembles with GABA_A receptor  and  subunits in Xenopus laevis oocytes and transfected mammalian cells to form functional GABA-gated channels. 11 GABA_A receptors, like 112s receptors, are modulated by pentobarbital and the steroid 5-pregnan-3-ol-20-one but, unlike 112s receptors, are insensitive to flunitrazepam. Additionally, 11 receptors exhibit rapid desensitization kinetics, as compared with 11 or 112s. Northern analysis demonstrates widespread expression of a large  subunit transcript in a variety of non-neuronal tissues and expression of a smaller transcript in brain and spinal cord. Sequence analysis demonstrated that the large transcript contained an unspliced intron, whereas the small transcript represents the mature mRNA, suggesting regulation of expression of the  subunit via neuronally restricted RNA splicing. In situ hybridization and immunocytochemistry reveal a pattern of expression in the brain restricted primarily to the hypothalamus, suggesting a role in neuroendocrine regulation, and also to subfields of the hippocampus, suggesting a role in the modulation of long term potentiation and memory.

Key words: GABA_A receptor; subunit; function; RNA splicing; hypothalamus: hippocampus

This article has been cited by other articles:

				R. W. Olsen and W. Sieghart International Union of Pharmacology. LXX. Subtypes of {gamma}-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update Pharmacol. Rev., September 1, 2008; 60(3): 243 - 260. [Abstract] [Full Text] [PDF]

				S. S. Sarang, S. M. Lukyanova, D. D. Brown, B. S. Cummings, S. R. Gullans, and R. G. Schnellmann Identification, Coassembly, and Activity of {gamma}-Aminobutyric Acid Receptor Subunits in Renal Proximal Tubular Cells J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 376 - 382. [Abstract] [Full Text] [PDF]

				J. J. Yi and M. D. Ehlers Emerging Roles for Ubiquitin and Protein Degradation in Neuronal Function Pharmacol. Rev., March 1, 2007; 59(1): 14 - 39. [Abstract] [Full Text] [PDF]

				B. L. Jones, P. J. Whiting, and L. P. Henderson Mechanisms of anabolic androgenic steroid inhibition of mammalian {varepsilon}-subunit-containing GABAA receptors J. Physiol., June 15, 2006; 573(3): 571 - 593. [Abstract] [Full Text] [PDF]

				D. A. Wagner, M. P. Goldschen-Ohm, T. G. Hales, and M. V. Jones Kinetics and Spontaneous Open Probability Conferred by the {epsilon} Subunit of the GABAA Receptor J. Neurosci., November 9, 2005; 25(45): 10462 - 10468. [Abstract] [Full Text] [PDF]

				O. A. Sergeeva, N. Andreeva, M. Garret, A. Scherer, and H. L. Haas Pharmacological Properties of GABAA Receptors in Rat Hypothalamic Neurons Expressing the {epsilon}-Subunit J. Neurosci., January 5, 2005; 25(1): 88 - 95. [Abstract] [Full Text] [PDF]

				J. Simon, H. Wakimoto, N. Fujita, M. Lalande, and E. A. Barnard Analysis of the Set of GABAA Receptor Genes in the Human Genome J. Biol. Chem., October 1, 2004; 279(40): 41422 - 41435. [Abstract] [Full Text] [PDF]

				F. Minier and E. Sigel Positioning of the {alpha}-subunit isoforms confers a functional signature to {gamma}-aminobutyric acid type A receptors PNAS, May 18, 2004; 101(20): 7769 - 7774. [Abstract] [Full Text] [PDF]

				P. Jin, D. Walther, J. Zhang, C. Rowe-Teeter, and G. K. Fu Serine 171, a Conserved Residue in the {gamma}-Aminobutyric Acid Type A (GABAA) Receptor {gamma}2 Subunit, Mediates Subunit Interaction and Cell Surface Localization J. Biol. Chem., April 2, 2004; 279(14): 14179 - 14183. [Abstract] [Full Text] [PDF]

				D. Berezhnoy, Y. Nyfeler, A. Gonthier, H. Schwob, M. Goeldner, and E. Sigel On the Benzodiazepine Binding Pocket in GABAA Receptors J. Biol. Chem., January 30, 2004; 279(5): 3160 - 3168. [Abstract] [Full Text] [PDF]

				P. Jin, J. Zhang, C. Rowe-Teeter, J. Yang, L. L. Stuve, and G. K. Fu Cloning and Characterization of a GABAA Receptor {gamma}2 Subunit Variant J. Biol. Chem., January 9, 2004; 279(2): 1408 - 1414. [Abstract] [Full Text] [PDF]

				S. W. Baumann, R. Baur, and E. Sigel Individual Properties of the Two Functional Agonist Sites in GABAA Receptors J. Neurosci., December 3, 2003; 23(35): 11158 - 11166. [Abstract] [Full Text] [PDF]

				S. W. Baumann, R. Baur, and E. Sigel Forced Subunit Assembly in alpha 1beta 2gamma 2 GABAA Receptors. INSIGHT INTO THE ABSOLUTE ARRANGEMENT J. Biol. Chem., November 22, 2002; 277(48): 46020 - 46025. [Abstract] [Full Text] [PDF]

				H. Iwama and T. Gojobori Identification of Neurotransmitter Receptor Genes Under Significantly Relaxed Selective Constraint by Orthologous Gene Comparisons Between Humans and Rodents Mol. Biol. Evol., November 1, 2002; 19(11): 1891 - 1901. [Abstract] [Full Text] [PDF]

				R.-Q. Huang and G. H. Dillon Functional Characterization of GABAA Receptors in Neonatal Hypothalamic Brain Slice J Neurophysiol, October 1, 2002; 88(4): 1655 - 1663. [Abstract] [Full Text] [PDF]

				S.-A. Thompson, P. B. Wingrove, L. Connelly, P. J. Whiting, and K. A. Wafford Tracazolate Reveals a Novel Type of Allosteric Interaction with Recombinant gamma -Aminobutyric AcidA Receptors Mol. Pharmacol., April 1, 2002; 61(4): 861 - 869. [Abstract] [Full Text] [PDF]

				J. Baufreton, M. Garret, S. Dovero, B. Dufy, B. Bioulac, and A. Taupignon Activation of GABAA Receptors in Subthalamic Neurons In Vitro: Properties of Native Receptors and Inhibition Mechanisms J Neurophysiol, July 1, 2001; 86(1): 75 - 85. [Abstract] [Full Text] [PDF]

				S. S. SARANG, M. D. PLOTKIN, S. R. GULLANS, B. S. CUMMINGS, D. F. GRANT, and R. G. SCHNELLMANN Identification of the {{gamma}}-Aminobutyric Acid Receptor {beta}2 and {beta}3 Subunits in Rat, Rabbit, and Human Kidneys J. Am. Soc. Nephrol., June 1, 2001; 12(6): 1107 - 1113. [Abstract] [Full Text]

				R. Erlitzki, Y. Gong, M. Zhang, and G. Minuk Identification of gamma -aminobutyric acid receptor subunit types in human and rat liver Am J Physiol Gastrointest Liver Physiol, October 1, 2000; 279(4): G733 - G739. [Abstract] [Full Text] [PDF]

				J. C. Jorge-Rivera, K. L. McIntyre, and L. P. Henderson Anabolic Steroids Induce Region- and Subunit-Specific Rapid Modulation of GABAA Receptor-Mediated Currents in the Rat Forebrain J Neurophysiol, June 1, 2000; 83(6): 3299 - 3309. [Abstract] [Full Text] [PDF]

				S. T. Sinkkonen, M. C. Hanna, E. F. Kirkness, and E. R. Korpi GABAA Receptor epsilon and theta Subunits Display Unusual Structural Variation between Species and Are Enriched in the Rat Locus Ceruleus J. Neurosci., May 15, 2000; 20(10): 3588 - 3595. [Abstract] [Full Text] [PDF]

				K. Baer, C. Essrich, J. A. Benson, D. Benke, H. Bluethmann, J.-M. Fritschy, and B. Luscher Postsynaptic clustering of gamma -aminobutyric acid type A receptors by the gamma 3 subunit in vivo PNAS, October 26, 1999; 96(22): 12860 - 12865. [Abstract] [Full Text] [PDF]

				A. R. Brooks-Kayal, M. D. Shumate, H. Jin, D. D. Lin, T. Y. Rikhter, K. L. Holloway, and D. A. Coulter Human Neuronal gamma -Aminobutyric AcidA Receptors: Coordinated Subunit mRNA Expression and Functional Correlates in Individual Dentate Granule Cells J. Neurosci., October 1, 1999; 19(19): 8312 - 8318. [Abstract] [Full Text] [PDF]

				S. Srinivasan, C. J. Nichols, G. M. Lawless, R. W. Olsen, and A. J. Tobin Two Invariant Tryptophans on the alpha 1 Subunit Define Domains Necessary for GABAA Receptor Assembly J. Biol. Chem., September 17, 1999; 274(38): 26633 - 26638. [Abstract] [Full Text] [PDF]

				T. R. Neelands and R. L. Macdonald Incorporation of the pi Subunit into Functional gamma -Aminobutyric AcidA Receptors Mol. Pharmacol., September 1, 1999; 56(3): 598 - 610. [Abstract] [Full Text]

				T. P. Bonnert, R. M. McKernan, S. Farrar, B. le Bourdelles, R. P. Heavens, D. W. Smith, L. Hewson, M. R. Rigby, D. J. S. Sirinathsinghji, N. Brown, et al. theta , a novel gamma -aminobutyric acid type A receptor subunit PNAS, August 17, 1999; 96(17): 9891 - 9896. [Abstract] [Full Text] [PDF]

				D. F. Owens, X. Liu, and A. R. Kriegstein Changing Properties of GABAA Receptor-Mediated Signaling During Early Neocortical Development J Neurophysiol, August 1, 1999; 82(2): 570 - 583. [Abstract] [Full Text] [PDF]

				A. Y. Valeyev, J. C. Hackman, A. M. Holohean, P. M. Wood, J. L. Katz, and R. A. Davidoff GABA-Induced Cl- Current in Cultured Embryonic Human Dorsal Root Ganglion Neurons J Neurophysiol, July 1, 1999; 82(1): 1 - 9. [Abstract] [Full Text] [PDF]

				J. Kapur and R. L. Macdonald Postnatal Development of Hippocampal Dentate Granule Cell gamma -Aminobutyric AcidA Receptor Pharmacological Properties Mol. Pharmacol., March 1, 1999; 55(3): 444 - 452. [Abstract] [Full Text]

				G. Penton-Rol, S. Orlando, N. Polentarutti, S. Bernasconi, M. Muzio, M. Introna, and A. Mantovani Bacterial Lipopolysaccharide Causes Rapid Shedding, Followed by Inhibition of mRNA Expression, of the IL-1 Type II Receptor, with Concomitant Up-Regulation of the Type I Receptor and Induction of Incompletely Spliced Transcripts J. Immunol., March 1, 1999; 162(5): 2931 - 2938. [Abstract] [Full Text] [PDF]

				S. T. Nett, J. C. Jorge-Rivera, M. Myers, A. S. Clark, and L. P. Henderson Properties and Sex-Specific Differences of GABAA Receptors in Neurons Expressing gamma 1 Subunit mRNA in the Preoptic Area of the Rat J Neurophysiol, January 1, 1999; 81(1): 192 - 203. [Abstract] [Full Text] [PDF]

				T. R. Neelands, J. L. Fisher, M. Bianchi, and R. L. Macdonald Spontaneous and gamma -Aminobutyric Acid (GABA)-Activated GABAA Receptor Channels Formed by epsilon  Subunit-Containing Isoforms Mol. Pharmacol., January 1, 1999; 55(1): 168 - 178. [Abstract] [Full Text]

				C. Sur, K. Quirk, D. Dewar, J. Atack, and R. McKernan Rat and Human Hippocampal alpha 5 Subunit-Containing gamma -Aminobutyric AcidA Receptors Have alpha 5beta 3gamma 2 Pharmacological Characteristics Mol. Pharmacol., November 1, 1998; 54(5): 928 - 933. [Abstract] [Full Text]

				T. Defazio and J. J. Hablitz Zinc and Zolpidem Modulate mIPSCs in Rat Neocortical Pyramidal Neurons J Neurophysiol, October 1, 1998; 80(4): 1670 - 1677. [Abstract] [Full Text] [PDF]

				E. A. Barnard, P. Skolnick, R. W. Olsen, H. Mohler, W. Sieghart, G. Biggio, C. Braestrup, A. N. Bateson, and S. Z. Langer International Union of Pharmacology. XV. Subtypes of gamma -Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Structure and Receptor Function Pharmacol. Rev., June 1, 1998; 50(2): 291 - 314. [Abstract] [Full Text] [PDF]

				J. L. Fisher and R. L. Macdonald The Role of an alpha  Subtype M2-M3 His in Regulating Inhibition of GABAA Receptor Current by Zinc and Other Divalent Cations J. Neurosci., April 15, 1998; 18(8): 2944 - 2953. [Abstract] [Full Text] [PDF]

				B. Ebert, S. A. Thompson, K. Saounatsou, R. McKernan, P. Krogsgaard-Larsen, and K. A. Wafford Differences in Agonist/Antagonist Binding Affinity and Receptor Transduction Using Recombinant Human gamma -Aminobutyric Acid Type A Receptors Mol. Pharmacol., December 1, 1997; 52(6): 1150 - 1156. [Abstract] [Full Text]

				P. B. Wingrove, S. A. Thompson, K. A. Wafford, and P. J. Whiting Key Amino Acids in the gamma  Subunit of the gamma -Aminobutyric AcidA Receptor that Determine Ligand Binding and Modulation at the Benzodiazepine Site Mol. Pharmacol., November 1, 1997; 52(5): 874 - 881. [Abstract] [Full Text]

				S. W. Baumann, R. Baur, and E. Sigel Subunit Arrangement of gamma -Aminobutyric Acid Type A Receptors J. Biol. Chem., September 21, 2001; 276(39): 36275 - 36280. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help