G protein-gated inwardly rectifying potassium (Kir3) channels are involved in 
regulating membrane excitability in the brain. Kir3 channels have been shown to 
play a role in learning, analgesia and drug addiction. Little is known about the 
cell surface regulation of Kir3 channels. Using a proteomics approach, we 
recently discovered that sorting nexin 27 (SNX27) associates with a subset of 
Kir3 channels. Sorting nexins have been implicated in trafficking of proteins 
through endosomal compartments. The single PDZ domain of SNX27 binds directly to 
the PDZ binding motif of Kir3 channels leading to their downregulation. Here, we 
examined the functional effect of SNX27b expression on different subunit 
combinations of the Kir3 family. Our results show that regulation of Kir3 
channels by SNX27 depends critically on the combination of Kir3 subunits. This 
type of subunit-specific regulation could be important for determining the 
extent of Kir3 inhibition in normal as well as diseased states, such as drug 
addiction.