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Glutamate Receptors (Mglurs) Within the Family Heteromeric Taste Receptor Are All Directly Activated by Amino Acids

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Glutamate Receptors (Mglurs) Within the Family Heteromeric Taste Receptor Are All Directly Activated by Amino Acids Ancestral reconstruction of the ligand-binding pocket of Family C G protein-coupled receptors Donghui Kuang†, Yi Yao†, David MacLean†, Minghua Wang†, David R. Hampson†‡§, and Belinda S. W. Chang¶ʈ Departments of †Pharmaceutical Sciences, ‡Pharmacology,¶Ecology and Evolutionary Biology, and ʈCell and Systems Biology, University of Toronto, Toronto, ON, Canada M5S 3M2 Edited by Gregory A. Petsko, Brandeis University, Waltham, MA, and approved August 1, 2006 (received for review June 7, 2006) The metabotropic glutamate receptors (mGluRs) within the Family heteromeric taste receptor are all directly activated by amino acids. C subclass of G protein-coupled receptors are crucial modulators of Amino acids also allosterically regulate the activity of the CaSR and synaptic transmission. However, their closest relatives include a GABAB receptors (14, 15). For example, although calcium is diverse group of sensory receptors whose biological functions are considered the primary endogenous ligand at the CaSR, the not associated with neurotransmission, raising the question of the calcium-induced responses are enhanced in the presence of amino evolutionary origin of amino acid-binding Family C receptors. A acids, which are thought to bind to a site analogous to the glutamate common feature of most, if not all, functional Family C receptors is site in the mGluRs (16). the presence of an amino acid-binding site localized within the A key parameter in the study of the evolution and interrelated- large extracellular Venus flytrap domain. Here, we used maximum ness of Family C receptors is the amino acid selectivity for one or likelihood methods to infer the ancestral state of key residues in several amino acids. The mGluRs are activated by glutamate, the amino acid-binding pocket of a primordial Family C receptor. whereas other Family C receptors, such as the T1R taste receptors These residues were reconstructed in the background of the fish and the fish 5.24 chemosensory receptor (8, 9, 17, 18), are broadly 5.24 chemosensory receptor, a broad-spectrum amino acid-acti- tuned to recognize most amino acids. Other Family C receptors vated receptor. Unlike the WT 5.24 receptor, which was not appear to be activated by smaller subsets of amino acids, for activated by mGluR agonists and displayed low sensitivity toward example, GPRC6A, which is activated most potently by arginine L-glutamate, the reconstructed ancestral receptor possessed a and lysine, and the CaSR, which is modulated most potently by pharmacological profile characterized by high affinity for both hydrophobic aromatic amino acids such as phenylalanine and L-glutamate and selective Group I mGluR agonists. This pharma- tryptophan. cological phenotype could be largely recapitulated by mutating The variable ligand activation profiles of Family C receptors raise only two residues in the 5.24 receptor-binding pocket. Our results the question as to the pharmacological phenotype of Family C suggest that this primordial Family C receptor may have arisen receptors and how the amino acid-binding pockets may have early in metazoan evolution and that it already was preadapted as evolved over time to fulfill specific roles in the context of neuro- a glutamate receptor for its later use at excitatory synapses in transmission versus sensory perception. In this study, molecular glutamate-mediated neurotransmission. modeling of selected Family C receptors, together with the results of previous pharmacological studies, were used to identify key metabotropic glutamate receptor ͉ primordial receptor ͉ residues in the binding pocket responsible for conferring amino acid olfactory receptor ͉ calcium-sensing receptor ͉ taste receptor ligand selectivity. Maximum likelihood͞Bayesian phylogenetic methods then were used to infer the residues in the binding pocket lutamate and GABA-mediated neurotransmission likely of the fish 5.24 chemosensory receptor, and the predicted ancestral- Gevolved early in the metazoan lineage concurrent with the binding pocket was reconstructed by using site-directed mutagen- evolution of the nervous system. Although basal metazoan lineages esis. Our results show that the predicted ancestral receptor pos- such as those leading to present-day sponges do not have fully sessed high affinity for L-glutamate and, surprisingly, it also was developed nervous systems, they do possess primitive neural nets potently activated by highly selective mGluRs agonists. These and hints of glutamate and GABA-mediated transmission (1, 2). findings suggest that the primordial Family C receptor may have These two neurotransmitters act at ligand-gated ion channels and been preadapted for use in glutamate-mediated transmission. the metabotropic glutamate receptors (mGluRs) and GABAB Results receptors in the Family C class of proteins within the G protein- coupled receptor (GPCR) superfamily (3). Family C receptors Phylogenetic Analysis and Ancestral Reconstruction. A phylogenetic mediate a wide spectrum of physiological processes ranging from analysis of the aligned sequences showed that members of Family the modulation of synaptic transmission to the perception of C receptors fall into three major classes: the mGluR class; a second sensory stimuli. In addition to the mGluRs and the GABA class consisting of the CaSR, the T1R taste receptors, and a group B of olfactory and putative pheromone sensory receptors; and a third receptor, other Family C members include the calcium-sensing more distant class consisting of the two GABA receptor subunits, receptor (CaSR), which participates in the regulation of calcium B which were used to root the tree (Fig. 1). This phylogeny resulted homeostasis in the body (4, 5), and a diverse group of sensory receptors. The latter group encompasses the fish 5.24 chemosen- sory receptor expressed in olfactory epithelium and other sensory Author contributions: D.K. and Y.Y. contributed equally to this work; D.R.H. and B.S.W.C. tissues of the fish, the mammalian T1R taste receptors present on designed research; D.K., Y.Y., D.M., M.W., D.R.H., and B.S.W.C. performed research; D.K., taste cells, and the V2R class of putative pheromone receptors Y.Y., D.M., M.W., D.R.H., and B.S.W.C. analyzed data; and D.R.H. and B.S.W.C. wrote the expressed in the vomeronasal organ (6–9). paper. The ligand-binding domain of Family C receptors, also known as The authors declare no conflict of interest. the ‘‘Venus flytrap domain,’’ is distantly related to the prokaryotic This paper was submitted directly (Track II) to the PNAS office. periplasmic-binding proteins involved in amino acid and nutrient Freely available online through the PNAS open access option. transport in bacteria (10, 11). Free amino acids act at Family C Abbreviations: CaSR, calcium-sensing receptor; (S)-DHPG, 3,5-dihydroxyphenylglycine; receptors as either direct-acting orthosteric agonists or as allosteric GPCRs, G protein-coupled receptors; mGluR, metabotropic glutamate receptor. modulators of receptor activity. The mGluRs, the 5.24 receptor, the §To whom correspondence should be addressed. E-mail: [email protected]. closely related GPRC6A receptor (8, 12, 13), and the T1R1͞T1R3 © 2006 by The National Academy of Sciences of the USA 14050–14055 ͉ PNAS ͉ September 19, 2006 ͉ vol. 103 ͉ no. 38 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0604717103 Downloaded by guest on September 25, 2021 HsT1R1 WAS TnT1R1 HsT1R2 Taste R 83/100 TnT1R2 TnT1R3 WAI HsT1R3 87/99 f5.24 WAI QNM DrZO6 HsGPRC6a AA-sensing R 100/100 100/81 MmGPRC6a GgGPRC6a TnCaSR TrCaSR WAI SaCaSR1 SsCaSR CaSR 100/100 HsCaSR SaCaSR2 Resurrected TnV2R1 ancestral WAI TrV2R1 TrV2R2 receptor 86/100 TrV2R3 TnV2R2 TrV2R4 CaV2R1 Pheromone R WAI CaV2R2 IpV2R RAI 74/76 TrV2R5 RrV2R 100/100 Mm2R AgmGluR DmmXr Group II AmmGluR HsmGluR2 TgmGluR2 TnmGluR HsmGluR3 TgmGluR3 TnmGluR DmmGluR AmmGluR CbmGluR CemGluR2 HsmGluR8 TgmGluR8 Group III HsmGluR7 mGluR RGK TnmGluR 100/100 IpmGluR HsmGluR6 HsmGluR4 CbmGluR CemGluR7 AmmGluR7 TnmGluR OmmGluR Group I TnmGluR HsmGluR1 HsmGluR5a GgmGluR5 CemGluR2 Cbm GluR RrGABAbR1 RrGABAbR2 GABAb Fig. 1. Phylogeny of Family C receptors used for statistical inference of binding pocket residues in ancestral proteins, with inferred ancestral residues at sites 78, 310, and 389 (amino acid numbering based on the 5.24 receptor sequence) indicated above the nodes, and bootstrap percentage value for parsimony͞ distance analyses indicated below the nodes (see Fig. 4 for tree sequences, accession numbers, and bootstrap values within each subgroup). Branch lengths of the phylogeny were estimated by using likelihood methods under the wagϩG model. from analyses of aligned protein sequences by using a variety of agonist binding to the mGluRs and the amino acid selectivity of methods, including maximum parsimony as well as neighbor- other Family C receptors is mediated via contacts between residues EVOLUTION joining and minimum evolution distance analyses. Only one node in the distal portion of the binding pocket and the side chains of the was found to differ across these different types of analyses (within amino acid ligands (12, 13, 16–18, 20–26). Collectively, these studies the V2R pheromone͞olfactory receptor group); this node was have demonstrated that only a small subset of binding-pocket collapsed to form a polytomy in further ancestral reconstruction residues act as critical determinants of ligand selectivity. studies. Average bootstrap values across all nodes shown in the We focused on the amino acids occupying three key positions in phylogeny were 85% and 91% in distance
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