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The Journal of Neuroscience, September 27, 2006, 26(39):9902-9912; doi:10.1523/JNEUROSCI.2897-06.2006

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Cellular/Molecular
-Arrestin2-Mediated Internalization of Mammalian Odorant Receptors

Anastasia Mashukova,¹ Marc Spehr,² Hanns Hatt,¹ and Eva M. Neuhaus¹

¹Cell Physiology and ²Emmy Noether Research Group, Cell Physiology, Ruhr-Universitaet Bochum, 44780 Bochum, Germany

Correspondence should be addressed to Eva M. Neuhaus, Cell Physiology, Ruhr-Universitaet Bochum, Universitaetsstrasse 150, D-44780 Bochum, Germany. Email: eva.neuhaus{at}rub.de

Odorant receptors comprise the biggest subfamily of G-protein-coupled receptors. Although the endocytic mechanisms of other G-protein-coupled receptors have been characterized extensively, almost nothing is known about the intracellular trafficking of odorant receptors. The present study describes the endocytic pathway of mammalian odorant receptors, which bind -arrestin2 with high affinity and are internalized via a clathrin-dependent mechanism. After prolonged odorant exposure, receptors are not targeted to lysosomal degradation but accumulate in recycling endosomes. Odorant-induced odorant receptor desensitization is promoted by cAMP-dependent protein kinase A phosphorylation and is dependent on serine and threonine residues within the third intracellular loop of the receptor. Moreover, -arrestin2 is redistributed into the dendritic knobs of mouse olfactory receptor neurons after treatment with a complex odorant mixture. Prolonged odorant exposure resulted in accumulation of -arrestin2 in intracellular vesicles. Adaptation of olfactory receptor neurons to odorants can be abolished by the inhibition of clathrin-mediated endocytosis, showing the physiological relevance of the here described mechanism of odorant receptor desensitization. A better understanding of odorant receptor trafficking and additional insight into the molecular determinants underlying the interactions of odorant receptors with -arrestin2 and other trafficking proteins will therefore be important to fully understand the mechanisms of adaptation and sensitization in the olfactory epithelium.

Key words: olfactory receptor; arrestin; olfactory epithelium; endocytosis; desensitization; receptor trafficking

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Received Feb. 8, 2006; revised Aug. 8, 2006; accepted Aug. 8, 2006.

Correspondence should be addressed to Eva M. Neuhaus, Cell Physiology, Ruhr-Universitaet Bochum, Universitaetsstrasse 150, D-44780 Bochum, Germany. Email: eva.neuhaus{at}rub.de

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