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J Physiol Volume 584, Number 3, 769-787, November 1, 2007 DOI: 10.1113/jphysiol.2007.142364
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CELLULAR

Microscopic kinetic determinants of macroscopic currents: insights from coupling and uncoupling of GABAA receptor desensitization and deactivation

 Matt T. Bianchi1, Emmanuel J. Botzolakis2, Kevin F. Haas3, Janet L. Fisher4 and Robert L. Macdonald3,5,6

1 Partners Neurology, Massachusetts General Hospital and Brigham and Women's Hospital, Boston, MA 02114, USA
2 Program in Neuroscience, Departments of
3 Neurology
5 Molecular Physiology and Biophysics
6 Pharmacology, Vanderbilt University, Nashville, TN 3723, USA
4 Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA

The time course of inhibitory postsynaptic currents (IPSCs) reflects GABAA receptor deactivation, the process of current relaxation following transient activation. Fast desensitization has been demonstrated to prolong deactivation, and these processes have been described as being ‘coupled’. However, the relationship between desensitization and deactivation remains poorly understood. We investigated the ‘uncoupling’ of GABAA receptor macroscopic desensitization and deactivation using experimental conditions that affected these two processes differently. Changing agonist affinity preferentially altered deactivation, changing agonist concentration preferentially altered macroscopic desensitization, and a pore domain mutation prolonged deactivation despite blocking fast desensitization. To gain insight into the mechanistic basis for coupling and uncoupling, simulations were used to systematically evaluate the interplay between agonist affinity, gating efficacy, and desensitized state stability in shaping macroscopic desensitization and deactivation. We found that the influence of individual kinetic transitions on macroscopic currents depended not only on model connectivity, but also on the relationship among transitions within a given model. In addition, changing single rate constants differentially affected macroscopic desensitization and deactivation, thus providing parsimonious kinetic explanations for experimentally observed uncoupling. Finally, these findings permitted development of an algorithmic framework for kinetic interpretation of experimental manipulations that alter macroscopic current properties.

(Received 2 August 2007; accepted after revision 31 August 2007; first published online 20 September 2007)
Corresponding author R. L. Macdonald: Department of Neurology, Vanderbilt University Medical Center, 6140 Medical Research Building III, 465 21st Ave, South Nashville, TN 37232-8552, USA. Email: robert.macdonald{at}vanderbilt.edu

M. T. Bianchi and E. J. Botzolakis contributed equally to the work. This paper has online supplemental material.






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