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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Maclean, David Hampson, David R. Kuang, Donghui Yao, Yi Wang, Minghua Chang, Belinda S. W. |
| Description | Author Affiliation: Kuang D ( Departments of Pharmaceutical Sciences, Pharmacology, Ecology and Evolutionary Biology, and Cell and Systems Biology, University of Toronto, Toronto, ON, Canada M5S 3M2.); |
| Abstract | The metabotropic glutamate receptors (mGluRs) within the Family C subclass of G protein-coupled receptors are crucial modulators of synaptic transmission. However, their closest relatives include a diverse group of sensory receptors whose biological functions are not associated with neurotransmission, raising the question of the evolutionary origin of amino acid-binding Family C receptors. A common feature of most, if not all, functional Family C receptors is the presence of an amino acid-binding site localized within the large extracellular Venus flytrap domain. Here, we used maximum likelihood methods to infer the ancestral state of key residues in the amino acid-binding pocket of a primordial Family C receptor. These residues were reconstructed in the background of the fish 5.24 chemosensory receptor, a broad-spectrum amino acid-activated receptor. Unlike the WT 5.24 receptor, which was not activated by mGluR agonists and displayed low sensitivity toward l-glutamate, the reconstructed ancestral receptor possessed a pharmacological profile characterized by high affinity for both l-glutamate and selective Group I mGluR agonists. This pharmacological phenotype could be largely recapitulated by mutating only two residues in the 5.24 receptor-binding pocket. Our results suggest that this primordial Family C receptor may have arisen early in metazoan evolution and that it already was preadapted as a glutamate receptor for its later use at excitatory synapses in glutamate-mediated neurotransmission. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 38 |
| Volume Number | 103 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2006-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Biological Evolution Receptors, Metabotropic Glutamate Chemistry Classification Animals Binding Sites Chemoreceptor Cells Glutamic Acid Metabolism Likelihood Functions Molecular Sequence Data Molecular Structure Phenotype Phylogeny Genetics Sequence Alignment Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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