G-protein coupled receptors Mc4r and Drd1a can serve as surrogate odorant receptors in mouse olfactory sensory neurons

In the mouse, most mature olfactory sensory neurons (OSNs) express one allele of one gene from the repertoire of 1100 odorant receptor (OR) genes, which encode G-protein coupled receptors (GPCRs). Axons of OSNs that express a given OR coalesce into homogeneous glomeruli, which reside at conserved positions in the olfactory bulb. ORs are intimately involved in ensuring the expression of one OR per OSN and the coalescence of OSN axons into glomeruli. But the mechanisms whereby ORs accomplish these diverse functions remain poorly understood. An experimental approach that has been informative is to substitute an OR genetically with another GPCR that is normally not expressed in OSNs, in order to determine in which aspects this GPCR can serve as surrogate OR in mouse OSNs. Thus far only the 132-adrenergic receptor (132AR, Ardb2) has been shown to be able to serve as surrogate OR in OSNs; the f32AR could substitute for the M71 OR in all aspects examined. Can other non-olfactory GPCRs function equally well as surrogate ORs in OSNs? Here, we have generated and characterized two novel gene-targeted mouse strains in which the mouse melanocortin 4 receptor (Mc4r) or the mouse dopamine receptor D1 (Drdla) is coexpressed with tauGFP in OSNs that express the OR locus M71. These alleles and strains are abbreviated as Mc4r M71-GFP and Drdla M71-GFP. We detected strong Mc4r or Drdla immunoreactivity in axons and dendritic knobs and cilia of OSNs that express Mc4r or Drdla from the M71 locus. These OSNs responded physiologically to cognate agonists for Mc4r (Ro27-3225) or Drdla (SKF81297), and not to the M71 ligand acetophenone. Axons of OSNs expressing Mc4r M71-GFP coalesced into glomeruli. Axons of OSNs expressing Drdla M71-GFP converged onto restricted areas of the olfactory bulb but did not coalesce into glomeruli. Thus, OR functions in OSNs can be substituted by Mc4r or Drdla, but not as well as by I32AR. We attribute the weak performance of Drdla as surrogate OR to poor OSN maturation.