A number of intrinsic amino acid sequences have been identified that control the intracellular trafficking of GIRK channels. GIRK2 contains a strong ER export signal (acidic residues) as well as an internalization (“VL”) motif39, enabling this subunit to form homotetramers or heteroteramers. GIRK1, on the other hand, lacks an ER export signal and must associate with another GIRK subunit (e.g. GIRK2 or GIRK3) to express on the plasma membrane24,39.. Although GIRK3 cannot form functional homotetramers, it can coassemble with GIRK1 or GIRK2 to form functional heterotetramers11,20,23,25. Unique to GIRK3, however, is a lysosomal targeting sequence (“YWSI”) that promotes degradation of GIRK channels39. Both GIRK2c and GIRK3 contain a class I PDZ binding motif, and interact directly with a novel PDZ-containing trafficking protein, sorting nexin 27 (SNX27)40. Association of SNX27 with GIRK3-containing channels leads to a reduction of GIRK signaling on the plasma membrane, most likely by promoting its internalization40. Whether GIRK2c and GIRK3 also interact with classical PDZ containing proteins, such as PSD95/SAP97, in neurons is unclear41,42. The interplay of these trafficking motifs suggests that GIRK2 plays a primary role in forming native GIRK currents while GIRK3 may regulate the availability of GIRK channels on the plasma membrane.
