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The Journal of Neuroscience, November 9, 2005, 25(45):10462-10468; doi:10.1523/JNEUROSCI.1658-05.2005

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Cellular/Molecular
Kinetics and Spontaneous Open Probability Conferred by the Subunit of the GABA_A 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

GABA_A 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

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Received April 26, 2005; revised September 28, 2005; accepted October 2, 2005.

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