J Physiol Society Membership
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Physiol Volume 532, Number 3, 673-684, May 1, 2001
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Akk, G.
Right arrow Articles by Steinbach, J. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Akk, G.
Right arrow Articles by Steinbach, J. H.
Journal of Physiology (2001), 532.3, pp. 673-684
© Copyright 2001 The Physiological Society

Pregnenolone sulfate block of GABAA receptors: mechanism and involvement of a residue in the M2 region of the alpha subunit


Gustav Akk, John Bracamontes and Joe Henry Steinbach


Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110, USA

  1. Neurosteroids are produced in the brain, and can have rapid actions on membrane channels of neurons. Pregnenolone sulfate (PS) is a sulfated neurosteroid which reduces the responses of the gamma-aminobutyric acid A (GABAA) receptor. We analysed the actions of PS on single-channel currents from recombinant GABAA receptors formed from alpha1, beta2 and gamma2L subunits.
  2. Currents were elicited by a concentration of GABA eliciting a half-maximal response (50 µM) and a saturating concentration (1 mM). PS reduced the duration of clusters of single-channel activity at either concentration of GABA.
  3. PS had no discernable effect on rapid processes: no effects were apparent on channel opening and closing, nor on GABA affinity, and a rapidly recovering desensitised state was not affected. Instead, PS produced a slowly developing block which occurred at a similar rate for receptors with open or closed channels and with one or two bound GABA molecules.
  4. The rate of block was independent of membrane potential, implying that the charged sulfate moiety does not move through the membrane field.
  5. Change in a specific residue near the intracellular end of the channel lining portion of the alpha1 subunit had a major effect on the rate of block. Mutation of the residue alpha1 V256S reduced the rate of block by 30-fold. A mutation at the homologous position of the beta2 subunit (beta2 A252S) had no effect, nor did a complementary mutation in the gamma2L subunit (gamma2L S266A). It seems likely that this residue is involved in a conformational change underlying block by PS, instead of forming part of the binding site for PS.



This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
G. Akk, P. Li, J. Bracamontes, D. E. Reichert, D. F. Covey, and J. H. Steinbach
Mutations of the GABA-A Receptor {alpha}1 Subunit M1 Domain Reveal Unexpected Complexity for Modulation by Neuroactive Steroids
Mol. Pharmacol., September 1, 2008; 74(3): 614 - 627.
[Abstract] [Full Text] [PDF]

Home page
 Biophys. JHome page
S. Mennerick, M. Lamberta, H.-J. Shu, J. Hogins, C. Wang, D. F. Covey, L. N. Eisenman, and C. F. Zorumski
Effects on Membrane Capacitance of Steroids with Antagonist Properties at GABAA Receptors
Biophys. J., July 1, 2008; 95(1): 176 - 185.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
V. Twede, A. L. Tartaglia, D. F. Covey, and B. A. Bamber
The Neurosteroids Dehydroepiandrosterone Sulfate and Pregnenolone Sulfate Inhibit the UNC-49 GABA Receptor through a Common Set of Residues
Mol. Pharmacol., November 1, 2007; 72(5): 1322 - 1329.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
P. Li, H.-J. Shu, C. Wang, S. Mennerick, C. F. Zorumski, D. F. Covey, J. H. Steinbach, and G. Akk
Neurosteroid migration to intracellular compartments reduces steroid concentration in the membrane and diminishes GABA-A receptor potentiation
J. Physiol., November 1, 2007; 584(3): 789 - 800.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
W. Li, X. Jin, D. F. Covey, and J. H. Steinbach
Neuroactive Steroids and Human Recombinant {rho}1 GABA Receptors
J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 236 - 247.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
P. Li, J. Bracamontes, B. W. Katona, D. F. Covey, J. H. Steinbach, and G. Akk
Natural and Enantiomeric Etiocholanolone Interact with Distinct Sites on the Rat {alpha}1beta2{gamma}2L GABAA Receptor
Mol. Pharmacol., June 1, 2007; 71(6): 1582 - 1590.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
G. Akk, P. Li, B. D. Manion, A. S. Evers, and J. H. Steinbach
Ethanol Modulates the Interaction of the Endogenous Neurosteroid Allopregnanolone with the {alpha}1beta2{gamma}2L GABAA Receptor
Mol. Pharmacol., February 1, 2007; 71(2): 461 - 472.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
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]

Home page
 Mol. Pharmacol.Home page
W. Li, D. F. Covey, J.-M. Alakoskela, P. K. J. Kinnunen, and J. H. Steinbach
Enantiomers of Neuroactive Steroids Support a Specific Interaction with the GABA-C Receptor as the Mechanism of Steroid Action
Mol. Pharmacol., June 1, 2006; 69(6): 1779 - 1782.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
P. Li, D. F. Covey, J. H. Steinbach, and G. Akk
Dual Potentiating and Inhibitory Actions of a Benz[e]indene Neurosteroid Analog on Recombinant {alpha}1beta2{gamma}2 GABAA Receptors
Mol. Pharmacol., June 1, 2006; 69(6): 2015 - 2026.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
L. Chen and M. Sokabe
Presynaptic Modulation of Synaptic Transmission by Pregnenolone Sulfate as Studied by Optical Recordings
J Neurophysiol, December 1, 2005; 94(6): 4131 - 4144.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
M. Horak, K. Vlcek, M. Petrovic, H. Chodounska, and L. Vyklicky Jr
Molecular Mechanism of Pregnenolone Sulfate Action at NR1/NR2B Receptors
J. Neurosci., November 17, 2004; 24(46): 10318 - 10325.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
J. W. Lynch
Molecular Structure and Function of the Glycine Receptor Chloride Channel
Physiol Rev, October 1, 2004; 84(4): 1051 - 1095.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
G. Akk, J. R. Bracamontes, D. F. Covey, A. Evers, T. Dao, and J. H. Steinbach
Neuroactive steroids have multiple actions to potentiate GABAA receptors
J. Physiol., July 1, 2004; 558(1): 59 - 74.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
Z. Mtchedlishvili and J. Kapur
A Presynaptic Action of the Neurosteroid Pregnenolone Sulfate on GABAergic Synaptic Transmission
Mol. Pharmacol., October 1, 2003; 64(4): 857 - 864.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
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]

Home page
 Mol. Pharmacol.Home page
S. Mennerick, C.-M. Zeng, A. Benz, W. Shen, Y. Izumi, A. S. Evers, D. F. Covey, and C. F. Zorumski
Effects on gamma -Aminobutyric Acid (GABA)A Receptors of a Neuroactive Steroid That Negatively Modulates Glutamate Neurotransmission and Augments GABA Neurotransmission
Mol. Pharmacol., October 1, 2001; 60(4): 732 - 741.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2001 The Physiological Society.