This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent experimental evidence indicates an important role of alpha2C adrenergic receptor (AR) in Raynaud Phenomenon (RP). This receptor subtype is poorly expressed at the plasma membrane at 37oC, accumulating in endoplasmic reticulum (ER) and Golgi apparatus. Alpha2C-AR traffic to the cell surface is greatly enhanced after cold exposure. Structural analysis indicate that alpha2C-AR has an unusual high number of arginine (R) residues in the third intracellular loop and in the C-terminus, organized in eleven putative arginine sorting motifs (RXR). When embedded in other proteins, this RXR motif has been shown to induce ER retention. Our preliminary experiments demonstrated that deletion of the eight putative RXR motifs from the third intracellular loop greatly enhanced alpha2C-AR transport at 30oC. Based on this observation, our overall hypothesis is that unique structural motifs in alpha2C-AR regulate its trafficking. The experimental plan aims to distinguish between the contributions of ER arrest and obstruction of transport from Golgi to the plasma membrane and it will elucidate the mechanisms involved in the alpha2C traffic modulation by identifying the RXR motifs conferring temperature sensitivity to alpha2C-AR transport and determining the molecular mechanisms involved in these effects. Further, the role of Rab8 and Rab14 GTPases in the temperature sensitive alpha2C-AR receptor plasma membrane expression will be studied. These studies will produce novel and important information regarding the molecular determinants of alpha2C-AR intracellular accumulation and may provide foundation for designing more effective therapeutic strategies in Raynaud Phenomenon.
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