Truncation releases olfactory receptors from the endoplasmic reticulum of heterologous cells

Olfactory receptors are difficult to express functionally in heterologous c ells. We found that olfactory receptors traffic poorly to the plasma membra ne even in cells with neuronal phenotypes, including cell lines derived fro m the olfactory epithelium. Other than mature olfactory receptor neurons, f ew cells appear able to traffic olfactory receptors to the plasma membrane. In human embryonic kidney 293 cells and Xenopus fibroblasts, olfactory rec eptor immunoreactivity overlapped with a marker for the endoplasmic reticul um (ER) but not with markers for the Golgi apparatus or endosomes. Except f or the ER, olfactory receptors were therefore absent from organelles normal ly involved in the plasma membrane trafficking of receptors. Olfactory rece ptors truncated prior to transmembrane domain VI were expressed in the plas ma membrane, however. Go-expression of the missing C-terminal fragment with these truncated receptors prevented their expression in the plasma membran e. Intramolecular interactions between N- and G-terminal domains joined by the third cytoplasmic loop appear to be responsible for retention of olfact ory receptors in the ER of heterologous cells. Our results are consistent w ith misfolding of the receptors but could also be explained by altered traf ficking of the receptors.