Previous studies support a role for SNX27 in regulating forward trafficking of signaling proteins. In cultured aortic cardiac cells, RNAi knockdown of SNX27 lowered β2-adrenergic receptor expression on the plasma membrane (Lauffer et al., 2010; Temkin et al., 2011). Similarly, reduced levels of SNX27 protein in a heterozygote SNX27-deficient mice (Snx27+/−) reduced forward trafficking of GluR1 and NR1 glutamate receptors in hippocampus (Wang et al., 2013). A more detailed analysis of β2-adrenergic receptor recycling revealed that sorting nexin 27 (SNX27) links β2-adrenergic receptors to the retromer tubule, which is important for recycling back to the plasma membrane (Temkin et al., 2011). In addition to the PDZ domain and PX domain, SNX27 contains a RA / FERM domain that is proposed to bind Ras-like GTPase proteins (Balana et al., 2013; Ghai et al., 2011); perhaps the RA domain recruits additional binding partners to regulate interaction with the retromer complex and trafficking from the early endosome. Using a proteomics approach, Steinberg et al. (2013) discovered over 100 cell surface proteins that required a SNX27–retromer to prevent lysosomal degradation and maintain surface levels. It will be important to establish if the same retromer pathway exists for GIRK channels in SNX27-mediated recycling.
