Abstract
BackgroundP-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP1) are membrane transporter proteins which function as efflux pumps at cell membranes and are considered to exert a protective function against the entry of xenobiotics. While evidence for Pgp and MRP transporter activity is reported for olfactory tissue, their possible interaction and participation in the olfactory response has not been investigated.Principal FindingsFunctional activity of putative MDR transporters was assessed by means of the fluorometric calcein acetoxymethyl ester (calcein-AM) accumulation assay on acute rat and mouse olfactory tissue slices. Calcein-AM uptake was measured as fluorescence intensity changes in the presence of Pgp or MRP specific inhibitors. Epifluorescence microscopy measured time course analysis in the olfactory epithelium revealed significant inhibitor-dependent calcein uptake in the presence of each of the selected inhibitors. Furthermore, intracellular calcein accumulation in olfactory receptor neurons was also significantly increased in the presence of either one of the Pgp or MRP inhibitors. The presence of Pgp or MRP1 encoding genes in the olfactory mucosa of rat and mouse was confirmed by RT-PCR with appropriate pairs of species-specific primers. Both transporters were expressed in both newborn and adult olfactory mucosa of both species. To assess a possible involvement of MDR transporters in the olfactory response, we examined the electrophysiological response to odorants in the presence of the selected MDR inhibitors by recording electroolfactograms (EOG). In both animal species, MRPs inhibitors induced a marked reduction of the EOG magnitude, while Pgp inhibitors had only a minor or no measurable effect.ConclusionsThe findings suggest that both Pgp and MRP transporters are functional in the olfactory mucosa and in olfactory receptor neurons. Pgp and MRPs may be cellular constituents of olfactory receptor neurons and represent potential mechanisms for modulation of the olfactory response.
Highlights
Among the numerous protein transporter systems present in many mucosal and epithelial tissue a few are toxically relevant efflux transporter proteins
The findings suggest that both Pgp and multidrug resistance-associated protein (MRP) transporters are functional in the olfactory mucosa and in olfactory receptor neurons
The experiments described above demonstrated a significant effect on calcein accumulation by Pgp and MRP-dependent inhibitors and the results suggest the presence of at least two functional multidrug resistance (MDR) transporters in the olfactory epithelium (OE)
Summary
Among the numerous protein transporter systems present in many mucosal and epithelial tissue a few are toxically relevant efflux transporter proteins They belong to the superfamily of binding cassette transporters (ABC transporters), transmembrane ATP-driven export pumps, and include amongst others two important members of two subfamilies, the P-glycoprotein (Pgp, gene symbol ABCB1) and the multidrug-associated resistance protein MRP1 (MRP1, gene symbol ABCC1). These proteins are especially well-known for their role in mediating the phenotype of multidrug resistance (MDR) seen in cancer cells where MDR is an acquired resistance against multiple chemotherapeutic drugs [1,2]. While evidence for Pgp and MRP transporter activity is reported for olfactory tissue, their possible interaction and participation in the olfactory response has not been investigated
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