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The Journal of Neuroscience, July 1, 2002, 22(13):5321-5327

Two Different Mechanisms of Disinhibition Produced by GABA_A Receptor Mutations Linked to Epilepsy in Humans

Matt T. Bianchi¹, Luyan Song², Helen Zhang¹, and Robert L. Macdonald^{2, 3, 4}

¹ Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan 48104-1687, and Departments of ² Neurology, ³ Molecular Physiology and Biophysics, and ⁴ Pharmacology, Vanderbilt University, Nashville, Tennessee 37212

The first mutations of the GABA_A receptor channel linked to familial epilepsy in humans were reported recently (Baulac et al., 2001; Wallace et al., 2001). Preliminary functional analysis of 122 GABA_A receptors expressed in Xenopus oocytes suggested that the 2 subunit R43Q mutation abolished current enhancement by the benzodiazepine, diazepam, and that the 2 subunit K289M mutation decreased current amplitudes. We used single-channel recording and concentration jump techniques applied to outside out patches to evaluate the impact of these mutations on GABA_A receptor channel function of the highly conserved rat ortholog subunits expressed in human embryonic kidney cells. When coexpressed with 1 and 3 subunits, no differences were observed between wild-type and mutant GABA_A receptor current activation rates or rates or extent of desensitization during prolonged (400 msec) GABA application (1 mM). Although deactivation after brief (5 msec) or prolonged (400 msec) GABA application was unaltered by the R43Q mutation, deactivation (a correlate of IPSC duration) was accelerated for the K289M mutation. Faster deactivation was likely a consequence of altered gating, because single-channel openings had shorter mean duration. Interestingly, the R43Q mutation did not alter diazepam potentiation. It did, however, substantially decrease current amplitude, which was not caused by decreased single-channel conductance or open time, suggesting reduced surface expression of functional receptors. The two 2 subunit mutations likely produce disinhibition and familial epilepsy by distinct mechanisms, suggesting that maintenance of neuronal inhibition depends not only on the peak amplitude of IPSCs, but also on their time course.

Key words: GABA_A receptor; mutation; epilepsy; concentration-jump; benzodiazepine; deactivation

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22135321-07$05.00/0

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