Expression and translocation of olfactory receptors

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Homo sapiens
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Olfactory receptors (ORs) are 7-pass transmembrane G protein-coupled receptors (GPCRs) located on dendritic cilia of olfactory sensory neurons (OSNs) of the olfactory epithelium (reviewed in Persuy et al. 2015). ORs are also located on cells of some other tissues (reviewed in Oh 2015). ORs bind ligands, called odorants, and activate downstream signaling through a heterotrimeric G-protein leading to opening of olfactory cyclic nucleotide-gated channels (CNG channels) and depolarization of the OSN. The human genome contains about 857 OR genes of which about 394 appear to be capable of encoding a functional OR. The remaining putative OR genes appear to be pseudogenes functionally inactivated by mutations.
Each OR binds a particular odorant or family of odorants. In order to provide odor discrimination, each OSN expresses only one OR gene and connects to specific olfactory bulb glomeruli according to the specific OR expressed (reviewed in Monahan and Lomvardas 2015, McClintock et al. 2020, Sakano et al. 2020). The choice of which OR gene to express is made by an epigenetic mechanism (reviewed in Bashkirova and Lomvardas 2019). Initially during OSN development, OR genes are heterochromatic. A few OR genes become weakly expressed and one then becomes dominant while all other OR genes remain silenced by heterochromatin. During activation of an OR gene, LHX2, LDB1, and EBF1 bind several (~60) intergenic enhancers located between OR genes on 18 chromosomes. The LHX2:LDB1:EBF1:enhancer complexes assemble into an interchromosomal super-enhancer that associates with the expressed OR gene and drives transcription.
Accumulation of OR protein in the endoplasmic reticulum membrane activates the unfolded protein response (UPR) that activates translation of ADCY3, which downregulates the histone methyltransferase KDM1A (LSD1) thereby preventing activation of any other OR genes (Lyons et al. 2013, Dalton et al. 2013).
Most OR proteins are inefficiently translocated from the endoplasmic reticulum membrane to the plasma membrane when they are expressed in heterologous cells. OSNs contain specific proteins that act as chaperones to increase subcellular translocation of at least some ORs (reviewed in Mainland and Matsunami 2012). The short isoform of RTP1 (RTP1S) and RTP2 bind the OR in the endoplasmic reticulum, are translocated with the OR to the plasma membrane, and remain at the plasma membrane. REEP1 more weakly increases translocation of ORs by an uncharacterized mechanism.

Literature References
PubMed ID Title Journal Year
29618184 System-Wide Expression and Function of Olfactory Receptors in Mammals

Oh, SJ

Genomics Inform 2018
24120133 Co-opting the unfolded protein response to elicit olfactory receptor feedback

Lomvardas, S, Dalton, RP, Lyons, DB

Cell 2013
25623335 Mammalian olfactory receptors: molecular mechanisms of odorant detection, 3D-modeling, and structure-activity relationships

Sanz, G, Thomas-Danguin, T, Tromelin, A, Pajot-Augy, E, Gibrat, JF, Persuy, MA

Prog Mol Biol Transl Sci 2015
32112394 Developmental regulation of olfactory circuit formation in mice

Sakano, H

Dev Growth Differ 2020
26359778 Monoallelic expression of olfactory receptors

Lomvardas, S, Monahan, K

Annu Rev Cell Dev Biol 2015
22434109 RAMP like proteins : RTP and REEP family of proteins

Matsunami, H, Mainland, J

Adv Exp Med Biol 2012
33075817 Maturation of the Olfactory Sensory Neuron and Its Cilia

Khan, N, Xie, C, Martens, JR, McClintock, TS

Chem Senses 2020
23870122 An epigenetic trap stabilizes singular olfactory receptor expression

Allen, WE, Barnea, G, Lomvardas, S, Tsai, L, Lyons, DB, Goh, T

Cell 2013
31491591 Olfactory receptor genes make the case for inter-chromosomal interactions

Lomvardas, S, Bashkirova, E

Curr Opin Genet Dev 2019
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