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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 alpha1beta2gamma2 GABA(A) receptors expressed in Xenopus oocytes suggested that the gamma2 subunit R43Q mutation abolished current enhancement by the benzodiazepine, diazepam, and that the gamma2 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 alpha1 and beta3 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 gamma2 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.
Angelotti,
Assembly of GABAA receptor subunits: analysis of transient single-cell expression utilizing a fluorescent substrate/marker gene technique.
1993, Pubmed
Angelotti,
Assembly of GABAA receptor subunits: analysis of transient single-cell expression utilizing a fluorescent substrate/marker gene technique.
1993,
Pubmed Baulac,
First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene.
2001,
Pubmed
,
Xenbase Bianchi,
Agonist Trapping by GABAA Receptor Channels.
2001,
Pubmed Bianchi,
Mutation of the 9' leucine in the GABA(A) receptor gamma2L subunit produces an apparent decrease in desensitization by stabilizing open states without altering desensitized states.
2001,
Pubmed Bianchi,
Structural determinants of fast desensitization and desensitization-deactivation coupling in GABAa receptors.
2001,
Pubmed Bross,
Protein misfolding and degradation in genetic diseases.
1999,
Pubmed Campos-Caro,
A single residue in the M2-M3 loop is a major determinant of coupling between binding and gating in neuronal nicotinic receptors.
1996,
Pubmed
,
Xenbase Chang,
Channel opening locks agonist onto the GABAC receptor.
1999,
Pubmed Chang,
Stoichiometry of a recombinant GABAA receptor.
1996,
Pubmed
,
Xenbase Dominguez-Perrot,
Recombinant GABAA receptor desensitization: the role of the gamma 2 subunit and its physiological significance.
1996,
Pubmed Fisher,
Single channel properties of recombinant GABAA receptors containing gamma 2 or delta subtypes expressed with alpha 1 and beta 3 subtypes in mouse L929 cells.
1997,
Pubmed Gomez,
Slow-channel transgenic mice: a model of postsynaptic organellar degeneration at the neuromuscular junction.
1997,
Pubmed
,
Xenbase Greenfield,
Expression of functional GABAA receptors in transfected L929 cells isolated by immunomagnetic bead separation.
1997,
Pubmed Haas,
GABAA receptor subunit gamma2 and delta subtypes confer unique kinetic properties on recombinant GABAA receptor currents in mouse fibroblasts.
1999,
Pubmed Jones,
Desensitized states prolong GABAA channel responses to brief agonist pulses.
1995,
Pubmed Keller,
Adjacent basic amino acid residues recognized by the COP I complex and ubiquitination govern endoplasmic reticulum to cell surface trafficking of the nicotinic acetylcholine receptor alpha-Subunit.
2001,
Pubmed Klausberger,
GABA(A) receptor assembly. Identification and structure of gamma(2) sequences forming the intersubunit contacts with alpha(1) and beta(3) subunits.
2000,
Pubmed Lewis,
Structure-function relationships of the human glycine receptor: insights from hyperekplexia mutations.
1999,
Pubmed
,
Xenbase Lynch,
Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel.
1997,
Pubmed Macdonald,
GABAA receptor channels.
1994,
Pubmed McKernan,
Which GABAA-receptor subtypes really occur in the brain?
1996,
Pubmed Pritchett,
Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology.
1989,
Pubmed Sieghart,
Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes.
1995,
Pubmed Sigel,
Role of the conserved lysine residue in the middle of the predicted extracellular loop between M2 and M3 in the GABA(A) receptor.
1999,
Pubmed
,
Xenbase Sigel,
The benzodiazepine binding site of GABAA receptors.
1997,
Pubmed Wallace,
Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures.
2001,
Pubmed
