![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 55, Issue 3, 411-423, March 1999
-Aminobutyric Acid Type C Receptor
Department of Pharmacology and Therapeutics and The Institute for
Biomolecular Science, University of South Florida, College of Medicine,
Tampa, Florida
Barbiturate sensitivity was imparted to the human 
1
homooligomeric 
-aminobutyric acid (GABA) receptor channel by
mutation of a tryptophan residue at position 328 (Trp328), which is
located within the third transmembrane domain. Substitutions of Trp328 with a spectrum of amino acids revealed that nearly all hydrophobic residues produced receptor channels that were both directly activated and modulated by pentobarbital with similar sensitivities. Previous studies with ligand-gated ion channels (including GABA) have
demonstrated that even conservative amino acid substitution within the
agonist-dependent activation domain (N-terminal extracellular domain)
can markedly impair agonist sensitivity. Thus, the lack of significant
variation in pentobarbital sensitivity among the Trp328 mutants attests to an intrinsic difference between pentobarbital- and the
GABA-dependent activation domain. Compared with the heterooligomeric
receptor channel, the mode of modulation for homooligomeric
Trp328 mutants by pentobarbital was more dependent on the GABA
concentration, yielding potentiation only at low concentrations of GABA
(fractions of their respective EC50 values), yet causing
inhibition at higher concentrations. Agonist-related studies have also
demonstrated that residue 328 plays an important role in
agonist-dependent activation, suggesting a functional interconnection
between the GABA and pentobarbital activation domains.
This article has been cited by other articles:
|
|
 |
|
  L. A. Gonzalez, M. B. Gatch, C. M. Taylor, C. L. Bell-Horner, M. J. Forster, and G. H. Dillon Carisoprodol-Mediated Modulation of GABAA Receptors: In Vitro and in Vivo Studies J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 827 - 837. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Gingrich, P. M. Burkat, and W. A. Roberts Pentobarbital Produces Activation and Block of {alpha}1{beta}2{gamma}2S GABAA Receptors in Rapidly Perfused Whole Cells and Membrane Patches: Divergent Results Can Be Explained by Pharmacokinetics J. Gen. Physiol., February 1, 2009; 133(2): 171 - 188. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Venkatachalan and C. Czajkowski A conserved salt bridge critical for GABAA receptor function and loop C dynamics PNAS, September 9, 2008; 105(36): 13604 - 13609. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Jenkins, I. A. Lobo, D. Gong, J. R. Trudell, K. Solt, R. A. Harris, and E. I. Eger II General Anesthetics Have Additive Actions on Three Ligand Gated Ion Channels Anesth. Analg., August 1, 2008; 107(2): 486 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Mercado and C. Czajkowski {gamma}-Aminobutyric Acid (GABA) and Pentobarbital Induce Different Conformational Rearrangements in the GABAA Receptor {alpha}1 and {beta}2 Pre-M1 Regions J. Biol. Chem., May 30, 2008; 283(22): 15250 - 15257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Hadley and J. Amin Rat {alpha}6beta2{delta} GABAA receptors exhibit two distinct and separable agonist affinities J. Physiol., June 15, 2007; 581(3): 1001 - 1018. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chen, K. Reilly, and Y. Chang Evolutionarily Conserved Allosteric Network in the Cys Loop Family of Ligand-gated Ion Channels Revealed by Statistical Covariance Analyses J. Biol. Chem., June 30, 2006; 281(26): 18184 - 18192. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.-Q. Huang, Z. Chen, and G. H. Dillon Molecular Basis for Modulation of Recombinant {alpha}1{beta}2{gamma}2 GABAA Receptors by Protons J Neurophysiol, August 1, 2004; 92(2): 883 - 894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. D. W. Morris and J. Amin Insight into the Mechanism of Action of Neuroactive Steroids Mol. Pharmacol., July 1, 2004; 66(1): 56 - 69. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Sessoms-Sikes, M. E. Hamilton, L.-X. Liu, D. M. Lovinger, and T. K. Machu A Mutation in Transmembrane Domain II of the 5-Hydroxytryptamine3A Receptor Stabilizes Channel Opening and Alters Alcohol Modulatory Actions J. Pharmacol. Exp. Ther., August 1, 2003; 306(2): 595 - 604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Engblom, B. X. Carlson, R. W. Olsen, A. Schousboe, and U. Kristiansen Point Mutation in the First Transmembrane Region of the beta 2 Subunit of the gamma -Aminobutyric Acid Type A Receptor Alters Desensitization Kinetics of gamma -Aminobutyric Acid- and Anesthetic-induced Channel Gating J. Biol. Chem., May 10, 2002; 277(20): 17438 - 17447. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Downie, F. Vicente-Agullo, A. Campos-Caro, T. J. Bushell, W. R. Lieb, and N. P. Franks Determinants of the Anesthetic Sensitivity of Neuronal Nicotinic Acetylcholine Receptors J. Biol. Chem., March 15, 2002; 277(12): 10367 - 10373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Serafini, J. Bracamontes, and J. H. Steinbach Structural domains of the human GABAA receptor {beta}3 subunit involved in the actions of pentobarbital J. Physiol., May 1, 2000; 524(3): 649 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. X. Carlson, A. C. Engblom, U. Kristiansen, A. Schousboe, and R. W. Olsen A Single Glycine Residue at the Entrance to the First Membrane-Spanning Domain of the gamma -Aminobutyric Acid Type A Receptor beta 2 Subunit Affects Allosteric Sensitivity to GABA and Anesthetics Mol. Pharmacol., March 1, 2000; 57(3): 474 - 484. [Abstract] [Full Text]
|
|
|
|
|
|
T. Yamakura, S. J. Mihic, and R. A. Harris Amino Acid Volume and Hydropathy of a Transmembrane Site Determine Glycine and Anesthetic Sensitivity of Glycine Receptors J. Biol. Chem., August 13, 1999; 274(33): 23006 - 23012. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
