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Details on Person ORs are a very large family of G Protein-Coupled Receptors (...
| Class:Id | Summation:8939785 |
|---|---|
| _displayName | ORs are a very large family of G Protein-Coupled Receptors (... |
| _timestamp | 2016-09-21 10:43:32 |
| created | [InstanceEdit:8939784] Jupe, Steve, 2016-09-21 |
| literatureReference | [LiteratureReference:8939765] Functional expression of olfactory-adrenergic receptor chimeras and intracellular retention of heterologously expressed olfactory receptors [LiteratureReference:8939737] Odorant receptor localization to olfactory cilia is mediated by ODR-4, a novel membrane-associated protein [LiteratureReference:8939730] Olfactory receptor trafficking involves conserved regulatory steps [LiteratureReference:8939751] RTP family members induce functional expression of mammalian odorant receptors [LiteratureReference:8939756] Members of RTP and REEP gene families influence functional bitter taste receptor expression [LiteratureReference:1297298] Expression of members of the putative olfactory receptor gene family in mammalian germ cells [LiteratureReference:8939753] Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network [LiteratureReference:8939759] A class of membrane proteins shaping the tubular endoplasmic reticulum [LiteratureReference:8939738] REEPs are membrane shaping adapter proteins that modulate specific g protein-coupled receptor trafficking by affecting ER cargo capacity |
| text | ORs are a very large family of G Protein-Coupled Receptors (GPCRs) that are selectively-expressed in olfactory epithelium. Mammalian Olfactory Receptor (OR) genes were discoved in rats (Buck & Axel 1991). ORs were predicted to be a family of GPCRs based on biochemical evidence that cAMP levels increased in olfactory neurons upon odor stimulation. Buck and Axel received a Nobel Prize for this and subsequent work (reviewed in Keller & Vosshall 2008). The ligands for ORs are diverse, ranging from chemical compounds to peptides. Intracellular signaling by OR proteins in mice and other mammals is mediated via direct interactions of OR proteins with an olfactory-specific heterotrimeric G Protein, G(olf), which includes the olfactory-specific G alpha S family protein GNAL (G-alpha-Olf). In mice, essentially all olfactory signaling requires G(olf); mouse G(olf) knockouts lack olfactory responses (Belluscio et al. 1998). There are two models for GPCR-G Protein interactions: 1) ligand-GPCR binding first, then binding to G Proteins; 2) "Pre-coupling" of GPCRs and G Proteins before ligand binding (Oldham & Hamm 2008). Both models may be true for certain GPCRs in different contexts. Pre-coupling is likely to be functionally important, as pre-coupling of receptor and G Protein allows much more rapid kinetic response once ligand is bound, because the ligand-bound receptor is immediately able to transduce the signal, rather than having to diffuse around within the plasma membrane until it encounters a G Protein to interact with (Oldham & Hamm 2008). The pre-coupling model is used here to characterise the reaction of the human ORs with G Proteins in the absence of ligand, because the ligands in humans are almost completely undocumented experimentally. In model systems many candidate OR genes have been shown to function in olfactory signaling (reviewed in Keller & Vosshall 2008). Experimental analysis of human OR genes is limited, though specific OR genes have been confirmed to mediate olfactory responses and signaling in humans for specific chemical odorants (Keller et al. 2007, Menashe et al. 2007). Rodents have about 1000 functional OR genes and many additional pseudogenes. Humans have around 960 OR genes; approximately half of these are pseudogenes (Keller & Vosshall 2008). Over 430 are expressed in human olfactory epithelium, including 80 expressed pseudogenes (Zhang 2007). When expressed in model cell systems, ORs are typically retained in the ER and degraded by the proteasome (McClintock et al. 1997). A study using Caenorhabditis elegans showed that transport of ORs to the cilia of olfactory neurons required the expression and association of ORs with a transmembrane protein, ODR4 (Dwyer et al. 1998). Co-transfection of rat ORs with ODR4 enhanced the transport and expression of the ORs at the cell-surface (Gimelbrant et al. 2001). These studies suggested that olfactory neurons might have a selective molecular machinery that promotes expression of ORs at the cells surface. Two human protein families have been identified as potential accessory proteins involved in the trafficking of ORs to the plasma membrane (Saito et al. 2004). Receptor transporting proteins 1 and 2 (RTP1, RTP2) both strongly induced expression of several ORs at the cell-surface. To a lesser extent, Receptor expression enhancing protein 1 (REEP1) also promoted cell-surface expression. These proteins are specifically expressed in olfactory neurons (Parmentier et al. 1992, Spehr et al. 2003). Other members of the RTP and REEP families have a widespread distribution. RTP3 and RTP4 have been shown to promote cell-surface expression of the bitter taste receptors, TAS2Rs (Behrens et al. 2006). REEP1 and REEP5 (also known as DP1) are involved in shaping of the ER by linking microtubule fibers to the ER (Park et al. 2010, Voeltz et al. 2006). Trafficking of Alpha2C-adrenergic receptor, but not Alpha2A, was enhanced by REEP1-2 and 6, which increased the capacity of ER cargo, thereby allowing more receptors to reach the cell-surface (Bjork et al. 2013). Unlike RTP1, REEP1-2 and 6 are only present in the ER and do not traffic to the plasma membrane. They specifically interact with the minimal/non-glycosylated forms of Alpha2C via an interaction with its C-terminus (Saito et al. 2004, Bjork et al. 2013). This suggests that REEPs may function as general modulators of the ER, rather than specifically interacting with GPCRs. |
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