Amino acid-activated family C G-protein coupled receptors
By: by Donghui Kuang.
Published: 2006
Language: eng
Number of pages: 160
ISBN-13: 9780494159033
Description: Amino acids act as either orthosteric agonists or as positive allosteric modulators of Family C G-protein coupled receptors (GPCRs). Family C receptors can be categorized into two primary groups based on amino acid sensitivity. A group that includes the metabotropic glutamate receptors (mG1uRs) was activated solely by L-glutamate, while a second group that includes an array of chemosensory receptors, responded to a broad spectrum of amino acid ligands. Phylogenetic analysis suggested an early separation of these two lineages of receptors. Two receptors in the latter class, the fish 5.24 receptor, and its putative mammalian orthologue, GPRC6A, both displayed a broad amino acid activation profile and a preference for basic amino acids.The molecular basis for ligand selectivity in Family C receptors was explored using amino acid sequence alignments, molecular modeling, mutagenesis, radioligand binding, and functional assays. Four conserved residues in the ligand binding pockets that interact with the alpha-amino group of the bound ligands are essential for amino acid recognition. Three additional sites at positions 78, 310, and 389 (numbering as in the 5.24 receptor) that establish bonds with the side-chain of the ligands are the primary determinants of amino acid selectivity within the family. An approach using "ancestral reconstruction" in order to trace the evolutionary history of molecular changes in protein structure, was carried out on the 5.24 receptor background. Using this approach, the ancestral residues at positions 78, 310, and 389 were inferred to be arginine, alanine, and isoleucine respectively. The pharmacological profile of the ancestral receptor displayed high affinity for L-glutamate and Group I mGluR-specific agonists. These findings suggested that the ancestral receptor of Family C GPCRs may have been pre-adapted for use in glutamate-mediated neurotransmission. Our results also suggest that this feature was further refined in the mGluR subfamily during evolution whereby the Group I mGluRs (mGluR1 and mGluR5) may have retained a more primitive configuration of the binding pocket compared to the other six mGluR receptor subtypes.
Notes: Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3617.

Thesis (Ph.D.)--University of Toronto, 2006.

Includes bibliographic references.

Electronic version licensed for access by U. of T. users.