Other accessory proteins

Accessory proteins are cell-specific biological factors that are necessary for the correct localization ofGPCRs to the plasma membrane and are distinct from RAMPS in that they are not involved in defining the pharmacological profile of GPCRs. The first description of accessory proteins came about from studies on opsins in which ninaA, a Drosophila melanogaster photoreceptor cyclophilin, was shown to be required for the localization of a subset of opsins to the rhabdomeres (Colley etal. 1991). NinaA and its mammalian homologue RanBP2 bind to specific opsins and act as chaperone proteins involved in the correct folding or transport of the receptor to the plasma membrane.

Another family of GPCRs that require cell-specific factors for their correct localization and expression is olfactory receptors. These receptors are extremely difficult to express in heterologous systems and only traffic to the plasma membrane in mature olfactory receptor neurons. For example, in Caenorhabditis elegans, the odr-10 gene encodes a seven transmembrane domain olfactory receptor that is inefficiently transported to the plasma membrane when expressed in heterologous cells (Zhang et al. 1997). This and other similar observations of inefficient expression of mammalian olfactory receptors led to the identification of the odr-4 and odr-8 genes in Caenorhabditis elegans (Dwyer et al. 1998). ODR-4 encodes a novel 445 amino acid protein that contains one C-terminal transmembrane domain, is expressed in chemosensory neurons and facilitates odorant receptor folding and/or trafficking to the plasma membrane. The molecular mechanism(s) involved in this facilitation are not known but several models have been proposed based on experimental observations. ODR-4 could serve as a chaperone protein to aid in protein folding, it could be necessary for sorting odorant receptors into the correct secretory vesicles, or it could be involved in targeting receptor-containing vesicles to the cilia (Dwyer et al. 1998). A more recent model has emerged in which olfactory receptor trafficking to the plasma membrane involves a two-step process in that one accessory protein may be necessary to release olfactory receptors from the endoplasmic reticulum to the golgi apparatus and/or endosomes, and a second accessory protein may be required for olfactory receptor release from the golgi/endosomes to the plasma membrane (Gimelbrant et al. 2001).

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