 |
The Journal of Neuroscience, November 9, 2005, 25(45):10462-10468; doi:10.1523/JNEUROSCI.1658-05.2005
 Previous Article | Next Article 
Cellular/Molecular
Kinetics and Spontaneous Open Probability Conferred by the  Subunit of the GABAA Receptor
David A. Wagner,1
Marcel P. Goldschen-Ohm,2
Tim G. Hales,3 and
Mathew V. Jones2
1Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin 53201, 2Department of Physiology, University of Wisconsin, Madison, Wisconsin 53706, and 3Departments of Pharmacology and Physiology, and Anesthesiology and Critical Care Medicine, The George Washington University, Washington, DC 20037
GABAA receptors mediate synaptic and extrasynaptic inhibition. Native receptors consist of  and  subunits, which are required for function, and another "modulatory" subunit, for example,  ,  , or  . Of these, the subunit has the most restricted distribution, confers resistance to neurosteroid and anesthetic modulation, and causes spontaneous channel opening. Little is known, however, about how affects receptor kinetics, which in turn shape responses to both ambient and synaptic GABA exposure. Here, we expressed human 21, 212, or 21 subunit combinations in human embryonic kidney 293 cells and used rapid solution exchange to study receptor kinetics in outside-out patches. The subunit greatly slowed deactivation and recovery after brief GABA pulses. During long, saturating GABA pulses, the rate of desensitization was slower for 21 and 212 than for 21. However, in 21, the final extent of desensitization was large compared with that of 212. Responses in 21, but not the others, were often followed by an "overshoot" above the baseline, suggesting that a fraction of channels are spontaneously open and are transiently silenced by receptor activation and subsequent desensitization. The baseline current and associated noise were reduced by picrotoxin, revealing that -containing channels are open  4% of the time in the absence of GABA. These results suggest that, if -containing receptors are expressed at synapses, the synaptic currents would be long-lasting but may rundown quickly under high-frequency activation. In addition, silencing of spontaneous openings by desensitization raises the possibility that tonic inhibition mediated by -containing receptors may be regulated by phasic inhibition.
Key words: kinetics; HEK293 cells; desensitization; deactivation; anesthetics; agonist-independent gating
Received April 26, 2005;
revised September 28, 2005;
accepted October 2, 2005.
This article has been cited by other articles:
|
|
|
|
 
M. R. McCartney, T. Z. Deeb, T. N. Henderson, and T. G. Hales
Tonically Active GABAA Receptors in Hippocampal Pyramidal Neurons Exhibit Constitutive GABA-Independent Gating
Mol. Pharmacol.,
February 1, 2007;
71(2):
539 - 548.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Bouairi, H. Kamendi, X. Wang, C. Gorini, and D. Mendelowitz
Multiple Types of GABAA Receptors Mediate Inhibition in Brain Stem Parasympathetic Cardiac Neurons In the Nucleus Ambiguus
J Neurophysiol,
December 1, 2006;
96(6):
3266 - 3272.
[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]
|
|
|
|
