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Expression and translocation of olfactory receptors

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-9752946

PubChem

R-HSA-9752946

Description

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.

Click on a node on the pathway to see its details. Glycoproteins are marked with a glycoprotein icon in their name.

SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

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UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
A3KFT3	Olfactory receptor 2M5	OR2M5 OR2M5P	view
A4D2G3	Olfactory receptor 2A25	OR2A25 OR2A25P OR2A27	view
A6NCV1	Olfactory receptor 6C74	OR6C74	view
A6ND48	Olfactory receptor 14I1	OR14I1 OR5BU1 OR5BU1P	view
A6NDH6	Olfactory receptor 5H15	OR5H15	view
A6NET4	Olfactory receptor 5K3	OR5K3	view
A6NF89	Olfactory receptor 6C6	OR6C6	view
A6NFC9	Putative olfactory receptor 2W5	OR2W5 OR2W5P	view
A6NH00	Olfactory receptor 2T8	OR2T8 OR2T8P	view
A6NHA9	Olfactory receptor 4C46	OR4C46	view

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