KCNE Regulation of K(+) Channel Trafficking - a Sisyphean Task?

Abstract

Voltage-gated potassium (Kv) channels shape the action potentials of excitable cells and regulate membrane potential and ion homeostasis in excitable and non-excitable cells. With 40 known members in the human genome and a variety of homomeric and heteromeric pore-forming α subunit interactions, post-translational modifications, cellular locations, and expression patterns, the functional repertoire of the Kv α subunit family is monumental. This versatility is amplified by a host of interacting proteins, including the single membrane-spanning KCNE ancillary subunits. Here, examining both the secretory and the endocytic pathways, we review recent findings illustrating the surprising virtuosity of the KCNE proteins in orchestrating not just the function, but also the composition, diaspora and retrieval of channels formed by their Kv α subunit partners.

Keywords: MinK-related peptides; endocytosis; trafficking; voltage-gated.

Figure 1

Impact of KCNE subunits on the composition and density of surface-expressed Kv channels. Pore-forming Kv α subunits, as listed in the key, form complexes in the ER that are trafficked through the Golgi to the plasma membrane (PM). KCNE1 and KCNE2 prevent the surface expression of homomeric N-type Kv channel complexes, but ensure heteromeric (mixed-α) complexes, that depending on their α subunit partners, may or may not include KCNEs. In this way, KCNE subunits form an intracellular checkpoint to modulate surface-expressed Kv channel composition. Similarly, KCNE1 dictates the dynamin-dependent endocytosis (DDE) of the KCNQ1-KCNE1 (I_Ks) complex. This process is further regulated: phosphorylation of KCNE1-S102 by Protein Kinase C (PKC) stimulates KCNQ1-KCNE1 DDE.