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- Title
Individual Properties of the Two Functional Agonist Sites in GABA[subA] Receptors.
- Authors
Baumann, Sabine W.; Baur, Roland; Sigel, Erwin
- Abstract
The members of the pentameric ligand-gated receptor channel family are involved in information transfer in synapses and the neuromuscular junction. They often contain several copies of the same subunit isoform. Here, we present a method to functionally dissect the role of individual subunits that occur in multiple copies in these receptors. Opening of the inherent chloride channel in the GABA[subA] receptor is achieved through the binding of two agonist molecules; however, it has been difficult to obtain information on the contribution of the two individual binding sites. The sites are both located β(+)/α(-) subunit interfaces, suggesting similar properties. One pair of subunits is flanked by γ and β (site 1) and the other by α and γ (site 2), the different environment possibly affecting the binding sites. Here, we used concatenated subunits and two point mutations of amino acid residues, each in α and β subunits, both located in the agonist binding pocket, to investigate the properties of these two sites. The sites were individually mutated, and consequences of these mutations on GABA and muscimol-induced channel opening and its competitive inhibition by bicuculline were studied. A model predicts that opening also occurs for receptors occupied with a single agonist molecule but is promoted approximately 60-fold in those occupied by two agonists and that site 2 has an approximately threefold higher affinity for GABA than site 1, whereas muscimol and bicuculline show some preference for site 1.
- Subjects
MOLECULES; GABA; LIGANDS (Biochemistry); CHLORIDE channels; MYONEURAL junction
- Publication
Journal of Neuroscience, 2003, Vol 23, Issue 35, p11158
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.23-35-11158.2003