Human Molecular Genetics Advance Access originally published online on February 12, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 7 771-780
DOI: 10.1093/hmg/ddh086
Amino-acid changes acquired during evolution by olfactory receptor 912-93 modify the specificity of odorant recognition
1IGH, CNRS UPR 1142, rue de la Cardonille, 34396 Montpellier cedex 5, France, 2CBS, CNRS-INSERM, 15, avenue Charles Flahault, 34093 Montpellier cedex 5, France and 3CCIPE, INSERM U469, rue de la Cardonille, 34094 Montpellier cedex 5, France
Received December 18, 2003; Revised January 26, 2004; Accepted February 2, 2004
The sense of smell in mammals can perceive and discriminate a wide variety of volatile odorants. Odorants bind to specific olfactory receptors (ORs) to initiate an action potential that transduces olfactory information to the olfactory cortex. We previously identified the structural motifs of odorant molecules (aliphatic 2- or 3-ketones) required to activate mouse OR912-93 by detection of the odorant response using calcium measurement in transfected cells. In order to study changes in the specificity of this receptor that might have occurred during evolution, we cloned the orthologous genes from six primate species and pig and assayed the encoded receptors for responses to odorants. Primate OR912-93 orthologs share 88–97% sequence identity. All the receptors responded to 2- and 3-heptanone except the squirrel-monkey OR, which responded only to 3-heptanone, and the human and orangutan ORs, which were not functional. Directed mutagenesis allowed us to convert the squirrel-monkey response to that of the other functional 912-93 ORs by substituting three amino acids in the second extracellular loop. Orangutan and human 912-93 ORs regained function after restoration of the arginine residue in the DRY motif required for G-protein activation. However, the human receptor was constitutively activated in the absence of ligand stimulation. Using natural mutants of the OR912-93 receptor, we provide evidence that squirrel-monkeys evolved towards a restriction of the specificity of this receptor and therefore that slight alterations in the sequence of a receptor can induce subtle changes in recognition specificity.
* To whom correspondence should be addressed. Email: giorgi{at}igh.cnrs.fr
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