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The Journal of Neuroscience, December 17, 2003, 23(37):11698-11710
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Cellular/Molecular
 Subunit Phosphorylation Selectively Increases Fast Desensitization and Prolongs Deactivation of  11 2L and 132L GABAA Receptor Currents
David J. Hinkle1 and
Robert L. Macdonald2,3,4
1Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan 48104-1687, and Departments of 2Neurology, 3Molecular Physiology and Biophysics, and 4Pharmacology, Vanderbilt University, Nashville, Tennessee 37212
We studied the effects of phosphorylation by protein kinase A (PKA) on GABAA receptors ( 1 1 2L and132L) transiently expressed in HEK 293T cells. Under conditions favorable for PKA activation, currents obtained using whole-cell patch clamp of lifted cells displayed increased rate and extent of the fast phases of desensitization, decreased rate of current deactivation after GABA removal, and prolongation of brief IPSC-like currents. Mutation of serine residues (1 S409, 3 S407, 3 S408) revealed that only 1 S409 and 3 S408 were critical for the modulatory effect of PKA on GABAA receptor currents. Additionally, repeated pulse inhibition was increased in receptors after mutation of the critical serine to glutamate and decreased when the serine was mutated to alanine. These data demonstrate that PKA phosphorylation modulated GABAA receptor currents by increasing fast phases of macroscopic desensitization and suggest a role for PKA in regulating GABAergic IPSC duration.
Key words: protein kinase A; chloride ion channel; GABAA receptor channels; rapid application; patch clamp; mutagenesis
Received May 16, 2003;
revised October 7, 2003;
accepted October 10, 2003.
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