Back to Search
Start Over
Developmental seizures and mortality result from reducing GABAA receptor α2-subunit interaction with collybistin
- Source :
- Nature Communications, 9 (1), Nature Communications, Vol 9, Iss 1, Pp 1-15 (2018)
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
Abstract
- Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABAARs) that are enriched at functionally diverse synapses via mechanisms that remain unclear. Using isothermal titration calorimetry and complementary methods we demonstrate an exclusive low micromolar binding of collybistin to the α2-subunit of GABAARs. To explore the biological relevance of collybistin-α2-subunit selectivity, we generate mice with a mutation in the α2-subunit-collybistin binding region (Gabra2-1). The mutation results in loss of a distinct subset of inhibitory synapses and decreased amplitude of inhibitory synaptic currents. Gabra2–1 mice have a striking phenotype characterized by increased susceptibility to seizures and early mortality. Surviving Gabra2-1 mice show anxiety and elevations in electroencephalogram δ power, which are ameliorated by treatment with the α2/α3-selective positive modulator, AZD7325. Taken together, our results demonstrate an α2-subunit selective binding of collybistin, which plays a key role in patterned brain activity, particularly during development.
- Subjects :
- 0301 basic medicine
Science
10050 Institute of Pharmacology and Toxicology
General Physics and Astronomy
610 Medicine & health
1600 General Chemistry
inhibitory synaptic GABAARs Gabra2–1 mice
Plasma protein binding
Neurotransmission
Inhibitory postsynaptic potential
medicine.disease_cause
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
0302 clinical medicine
1300 General Biochemistry, Genetics and Molecular Biology
medicine
lcsh:Science
Receptor
Mutation
Multidisciplinary
biology
Chemistry
GABAA receptor
HEK 293 cells
General Chemistry
3100 General Physics and Astronomy
3. Good health
Cell biology
030104 developmental biology
biology.protein
570 Life sciences
lcsh:Q
Collybistin
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....d703ccf51db8d383cbe424bb01aa9788