Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2002 Nov 12;9923:15170-5. doi: 10.1073/pnas.212320199.
Show Gene links
Show Anatomy links
Altered kinetics and benzodiazepine sensitivity of a GABAA receptor subunit mutation [gamma 2(R43Q)] found in human epilepsy.
Bowser DN
,
Wagner DA
,
Czajkowski C
,
Cromer BA
,
Parker MW
,
Wallace RH
,
Harkin LA
,
Mulley JC
,
Marini C
,
Berkovic SF
,
Williams DA
,
Jones MV
,
Petrou S
.
???displayArticle.abstract???
The gamma-aminobutyric acid type A (GABA(A)) receptor mediates fast inhibitory synaptic transmission in the CNS. Dysfunction of the GABA(A) receptor would be expected to cause neuronal hyperexcitability, a phenomenon linked with epileptogenesis. We have investigated the functional consequences of an arginine-to-glutamine mutation at position 43 within the GABA(A) gamma(2)-subunit found in a family with childhood absence epilepsy and febrile seizures. Rapid-application experiments performed on receptors expressed in HEK-293 cells demonstrated that the mutation slows GABA(A) receptor deactivation and increases the rate of desensitization, resulting in an accumulation of desensitized receptors during repeated, short applications. In Xenopus laevis oocytes, two-electrode voltage-clamp analysis of steady-state currents obtained from alpha(1)beta(2)gamma(2) or alpha(1)beta(2)gamma(2)(R43Q) receptors did not reveal any differences in GABA sensitivity. However, differences in the benzodiazepine pharmacology of mutant receptors were apparent. Mutant receptors expressed in oocytes displayed reduced sensitivity to diazepam and flunitrazepam but not the imidazopyridine zolpidem. These results provide evidence of impaired GABA(A) receptor function that could decrease the efficacy of transmission at inhibitory synapses, possibly generating a hyperexcitable neuronal state in thalamocortical networks of epileptic patients possessing the mutant subunit.
Barnard,
International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.
1998, Pubmed
Barnard,
International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.
1998,
Pubmed
Baulac,
First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene.
2001,
Pubmed
,
Xenbase
Berkovic,
Genetics of the epilepsies.
2001,
Pubmed
Bianchi,
Two different mechanisms of disinhibition produced by GABAA receptor mutations linked to epilepsy in humans.
2002,
Pubmed
,
Xenbase
Biervert,
A potassium channel mutation in neonatal human epilepsy.
1998,
Pubmed
,
Xenbase
Biervert,
Structural and mutational analysis of KCNQ2, the major gene locus for benign familial neonatal convulsions.
1999,
Pubmed
Boileau,
Molecular dissection of benzodiazepine binding and allosteric coupling using chimeric gamma-aminobutyric acidA receptor subunits.
1998,
Pubmed
,
Xenbase
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Buhr,
Subtle changes in residue 77 of the gamma subunit of alpha1beta2gamma2 GABAA receptors drastically alter the affinity for ligands of the benzodiazepine binding site.
1997,
Pubmed
,
Xenbase
Charlier,
A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family.
1998,
Pubmed
Clements,
Transmitter timecourse in the synaptic cleft: its role in central synaptic function.
1996,
Pubmed
Cromer,
Anxiety over GABA(A) receptor structure relieved by AChBP.
2002,
Pubmed
Draguhn,
Functional and molecular distinction between recombinant rat GABAA receptor subtypes by Zn2+.
1990,
Pubmed
Harkin,
Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus.
2002,
Pubmed
,
Xenbase
Jones,
Desensitized states prolong GABAA channel responses to brief agonist pulses.
1995,
Pubmed
Lerche,
A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions.
1999,
Pubmed
,
Xenbase
Lerche,
Ion channels and epilepsy.
2001,
Pubmed
McCormick,
On the cellular and network bases of epileptic seizures.
2001,
Pubmed
Mehta,
An update on GABAA receptors.
1999,
Pubmed
Phillips,
Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q 13.2.
1995,
Pubmed
Phillips,
A de novo mutation in sporadic nocturnal frontal lobe epilepsy.
2000,
Pubmed
Phillips,
CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy.
2001,
Pubmed
,
Xenbase
Singh,
A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.
1998,
Pubmed
Smart,
GABAA receptors are differentially sensitive to zinc: dependence on subunit composition.
1991,
Pubmed
Snead,
Absence epilepsy: advances in experimental animal models.
1999,
Pubmed
Steinlein,
A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.
1995,
Pubmed
Steinlein,
An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy.
1997,
Pubmed
Steriade,
Thalamocortical oscillations in the sleeping and aroused brain.
1993,
Pubmed
Wallace,
Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B.
1998,
Pubmed
,
Xenbase
Wallace,
Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus.
2001,
Pubmed
Wallace,
Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures.
2001,
Pubmed
Wingrove,
Key amino acids in the gamma subunit of the gamma-aminobutyric acidA receptor that determine ligand binding and modulation at the benzodiazepine site.
1997,
Pubmed
,
Xenbase
